Cardiovascular risk associated with sodium-containing medicines

Introduction: It is widely recognized that excess sodium intake increases the risk of hypertension, and this subsequently increases the risk of cardiovascular disease. Although efforts are being made to reduce sodium intake in the population in general, there are concerns that a considerable sodium load can be ingested via certain effervescent, dispersible, and soluble formulations of medicines.

Areas covered: Reducing dietary sodium intake in the general population has resulted in a significant reduction in cardiovascular disease outcomes. However, no previous studies have highlighted the potential risk of cardiovascular disease by taking sodium-containing medicines such as soluble forms of aspirin, paracetamol, ibuprofen, and other common drugs. We recently conducted a nested case-control study in the UK general population using the UK Clinical Practice Research Datalink to study the long-term use of sodium-containing medicines and cardiovascular outcomes. The results showed that compared with standard formulations, patients who took sodium-containing medicines were 16% more likely to develop cardiovascular events (OR = 1.16, 95% CI 1.12 – 1.21). The risks for stroke and hypertension were even higher, (1.22 [1.16 – 1.29] and 7.18 [6.74 – 7.65]), respectively.

Expert opinion: Sodium-containing formulations should be prescribed with caution only if the perceived benefits outweigh the risks.     

Pharmacovigilance during the pre-approval phases: an evolving pharmaceutical industry model in response to ICH E2E, CIOMS VI, FDA and EMEA/CHMP risk-management guidelines.

Pharmacovigilance science has traditionally been a discipline focussed on the postmarketing or post-authorisation period, with due attention directed towards pre-clinical safety data, clinical trials and adverse events. As the biological sciences have evolved, pharmacovigilance has slowly shifted toward earlier, proactive consideration of risks and potential benefits of drugs in the pre- and peri-approval stages of drug development, leading to a maturing of drug safety risk management. Further advances in biology, pharmacology and improvements in computational applications to medicine have led to the development of more complex medicines previously unobtainable and have also permitted a more thorough assessment of risks and potential benefits even earlier in the development process. Elevated public concern with the safety of more sophisticated medicines, combined with new science, have led pharmaceutical innovators, regulators and healthcare professionals to collaborate to develop guidelines, which drive enhanced pharmacovigilance and safety risk management earlier in drug development. In this paper, we review international guidelines on pharmacovigilance planning applicable to the pre-approval phases of medicines development and provide author opinion on these guidelines' potential drug safety implications. We discuss the possible evolution of a pharmaceutical industry model to respond to these guidelines; a view on multidisciplinary safety management teams is provided to encourage refinement of safety-signal identification and risk assessment early in drug development and to communicate important safety concerns to internal research efforts, patients, investigators and regulators. We further describe these functions in the context of the complexities of vulnerable populations, including the example of medicines research for paediatric populations. We also discuss the special role of epidemiology in pre-approval drug development and the impact on epidemiological science of changes to the pharmacovigilance paradigm.     

儿科超说明书用药现状与对策分析

摘 要通过归纳总结国内外儿科超说明书用药现状、原因及管理政策,提出规范我国儿科超说明书用药的对策。目前,世界发达国家基本上都对药品超说明书使用进行立法或实行相应政策,而我国对超说明书用药尚缺乏国家层面上的统一管理。儿科超说明书用药风险高,我国应针对超说明书用药原因,借鉴发达国家的管理方式,通过制定使用原则、分级管理、鼓励临床试验完善说明书信息等政策,降低儿科超说书用药风险,保障儿童用药安全。     

Safety concerns with current treatments for psoriasis in the elderly

ABSTRACT

Introduction: The approach to manage psoriasis in the elderly (ages ≥65 years) patients can be challenging. They often suffer from multiple comorbidities and polypharmacy with possible adverse effects and undergo a progressive functional impairment of the immune system that increases susceptibility to infections as well as to auto-reactivity. Despite the increasing aging of the general population and although several therapies are currently available for psoriasis treatment, data regarding their use and tolerability in the elderly are quite limited.

Areas covered: This review focuses on topical and systemic therapies that have been investigated in elderly patients in order to provide their safety profile in this population.

Expert opinion: Conventional systemic therapies in elderly patients should be carefully dispensed and the correct dosage individually determined, taking into account the metabolism changes, organ impairment, comorbidities, concomitant medications, and contraindications. Apremilast, due to its satisfactory safety profile and low risk of drug interactions, results as an appropriate treatment option for elderly patients. Biologics (TNF-α, IL-12/23, IL-17, and IL-23 inhibitors) come out as safe and long-term options for the management of these patients resulting not associated with a higher risk of adverse events.     

Factors influencing the implementation of medicine risk communications by healthcare professionals in clinical practice: A systematic review

BackgroundRegulatory medicines risk communications aim to prevent patient harm through the dissemination of safety information to healthcare professionals (HCPs), patients, and the public. Evidence suggests that in addition to implementing the required changes, HCPs also respond to these communications through unintended and unwarranted actions and behaviours such as stopping medicine courses unnecessarily, and blanket actions spilling over to unintended patients' populations. Misunderstanding and mis-implementation of medicines risk communications could jeopardise patients’ safety and clinical outcomes. Therefore, it is important to understand the determinants that affect HCPs responses to medicines risk communications. This systematic review aims to identify the factors that affect the implementation of risk communications by healthcare professionals.MethodsFifteen databases, including EMBASE, PubMed, Scopus, Web of science, CINAHL PLUS were searched in April–May 2018, and the search was updated again in June 2021 to identify studies reporting on factors influencing HCPs' uptake of medicine risk alerts. We used keywords such as risk communication, safety update, and safety regulation. Studies were excluded if they did not involve pharmacovigilance or patient safety alerts; or if they only focused on measuring HCPs' practice after alerts; or evaluating the effectiveness of risk minimisation measures without reporting on factors affecting HCPs’ actions. Studies relating to occupational hazards, case reports, interventional studies, and studies not involving HCPs were also excluded. The Mixed Method Appraisal Tool (MMAT) was used to assess the quality of the included studies. A Narrative synthesis approach was undertaken using thematic analysis and concept mapping, followed by a critical reflection of the synthesis.ResultsTwenty-eight studies met our criteria and were included in the synthesis. We identified four themes summarising the factors influencing HCPs’ implementation of risk communications. These include HCPs: knowledge of medicine alerts; perceptions of alerts; attitudes, and concerns regarding medicine alerts; and the self-reported impact of these alerts. Our concept mapping exercise identified key interactions between different stakeholders, and these interactions determine HCPs' implementation of medicine risk communications. These stakeholders comprise of alert developers, including the sources and senders of safety information, and the receivers of safety information including health care institutions, HCPs, patients and their carers.ConclusionsHealthcare professionals are crucial to translating risk communication messages into clinical practice. However, if they have inadequate information about the content of the alert, and have inaccurate perceptions about the alert, they may not implement the required clinical changes as intended. Communication of medicine risk alerts does not always translate into improved patient care, due to a complex interaction between stakeholders involved in the creation and implementation of these alerts. These complex interactions should be the subject of future research efforts to understand the alert-implementation trajectory and identify the mediators for change and interventions to improve implementation.     

Clozapine protocol: a collective approach to use of an unregistered medicine.

We describe a protocol for the use of an unregistered antipsychotic medicine, clozapine, in a mental health service. Traditionally, prescribing of unregistered medicines has been a matter between prescriber and patient alone. However, clozapine carries a high risk of agranulocytosis and its use requires strict adherence to monitoring procedures. Persons most likely to benefit from it include many who, because of their psychosis, may be unable to give truly informed consent or to react appropriately to adverse reactions. We have designed a protocol which seeks to ensure that this medicine is given only to those whose severity of illness and lack of response to all other reasonable treatment outweighs the risk of agranulocytosis, that it is used with maximum safety and that only persons who have been shown to benefit from the medicine continue to receive it after an initial trial. Although this protocol has been accepted by the medical staff, questions of clinical autonomy and liability in the event of medical misadventure remain.     

Safety and efficacy of over- the-counter cough and cold medicines for use in children

Importance of the field: Over-the-counter (OTC) cough and cold medications have been used widely for years and continue to be a preferred choice for temporary relief of symptoms of upper respiratory tract infections in children. These medications are being placed under extraordinary scrutiny in the pediatric population due to the lack of conclusive evidence about their therapeutic efficacy and increased reports of associations with serious adverse events and even mortality.

Areas covered in this review: A PubMed search was conducted to identify articles published up to August 2009 describing the efficacy and safety of OTC cough and cold medications in children. The objective was to provide an overview of the relevant literature and regulatory history and to comment on the available data on this important topic.

What the reader will gain: The paper provides a detailed up-to-date review of the key efficacy and safety studies published on the subject. In addition, the reader is presented with an overview of the regulatory history and recent developments surrounding the use of OTC cough and cold medications in children in the US.

Take home message: This review confirms the lack of efficacy of OTC cough and cold products in children and reaffirms that although the overall incidence of related serious adverse events is low, such events continue to occur. The conclusions in this paper support a recommendation that OTC cough and cold medications should not be given to infants and very young children. Furthermore, additional research is needed to evaluate the safety and efficacy of these medicines in the broader pediatric population.     

Nonclinical strategy considerations for safety pharmacology: evaluation of biopharmaceuticals

Introduction: Biopharmaceuticals, such as monoclonal antibodies and recombinant peptides, are important therapeutics to treat human disease. Key features of biopharmaceuticals that make them innovative medicines are their clinical effectiveness, high specificity for their human target, long half-life and target coverage, and low risk for “off-target” pharmacology.

Areas covered: This paper describes nonclinical safety pharmacology assessment of biopharmaceuticals with an emphasis on special considerations needed for these agents. Insight is provided on various approaches to conduct safety pharmacology studies for such therapeutics, including appropriate integration into non-rodent toxicity studies.

Expert opinion: The safety pharmacology evaluation of biopharmaceuticals requires a science-based, case-by-case approach, as each biological modality will have unique pharmacological characteristics that influence the overall nonclinical safety assessment strategy. The integration of safety pharmacology endpoints into general (repeat-dose) toxicity studies is a rational paradigm for assessing potential changes in the cardiovascular, central nervous, and respiratory systems, but requires thoughtful and practical planning. In some cases, especially based on target-pharmacology concerns, dedicated and optimally designed safety pharmacology studies may be needed to assess the functional risk of a new biopharmaceutical. For example, cardiovascular telemetry studies may be needed to detect small changes in arterial blood pressure after acute and chronic exposure.     

Adalimumab in children and adolescents with severe plaque psoriasis: a safety evaluation

ABSTRACT

Introduction: Psoriasis is a chronic inflammatory systemic disease that affects 2% of the population and is associated with an important physical and physiological burden. About 0.5–2% of psoriatic cases onset during the pediatric age range, and often it’s not diagnosed until adulthood. Adalimumab is an antitumor necrosis factor monoclonal antibody approved for use in children in 2008 and now it was used in several diseases in rheumatology, gastroenterology, and in dermatology.

Areas covered: The purpose of this article was to summarize what has been described in the literature so far, about safety in the use of adalimumab in pediatric psoriasis. The presented data was extrapolated from a literature review from PubMed searches (using words ‘pediatric psoriasis,’ ‘adalimumab children,’ ‘adalimumab safety,’ ‘pediatric psoriasis treatment,’ ‘adalimumab clinical trial’), treatment guidelines, and reports from European and United States regulatory agencies.

Expert opinion: Actually there are some biologic agents for the treatment of pediatric psoriasis, but the lack of safety data from controlled trials is evident. The safety data on the use of adalimumab in pediatric psoriasis was taken from long-term studies in the adult population. These studies confirm the data on the safety of the drug as it is also supported by several works on real-life.     

Use of Medicines that Influence Falls or Fractures in a Residential Home Setting

Objective: To study the pattern of use of medicines that may contribute to, or protect against, falls and fractures in the setting of a UK residential home population, and to compare the results with a similar study conducted in 2001.Setting and method: A cross-sectional survey was conducted in 2003 in 18 residential homes. A trained community pharmacist visited the homes to retrieve information about use of medicines whilst demographic details were provided by the residential home staff.Main outcome measure: The proportion of patients who were prescribed medicines with a potential positive benefit in preventing fractures, and medicines that may cause elderly people to fall.Results: The study population consisted of 581 residents. Compared to the 2001 study, the use of both calcium and vitamin D had increased significantly (8.3% versus 2.1%). Although, the overall prescribing of psychotropics in 2003 was relatively low, there was a trend for increased prescribing of these medicines which have been identified as risk factors for falling.Conclusion: In a residential home setting in the UK, the use of psychotropic drugs is not uncommon, whereas there is limited use of drugs that have the potential for preventing morbidity associated with falls.     

妊娠期用药对孕产妇妊娠结局影响及随访研究

目的 探讨孕产妇妊娠期用药现状及用药安全性，探索妊娠期药物咨询门诊的工作模式和数据积累。方法 将2021年10月—2022年12月在浙江大学医学院附属第一医院妊娠哺乳期用药咨询门诊所有接诊的孕产妇作为研究对象，记录其姓名、年龄、联系方式、末次月经以及妊娠期的药物使用情况，评估研究人群的用药概况及用药安全性，并对使用药物风险进行分析，整理临床药师的干预措施并对其妊娠结局进行随访研究。结果 经过筛选共纳入179名咨询孕产妇，研究人群中80%的患者是在未知妊娠状态下使用了药物，人均用药3种，最常见的用药原因为上呼吸道感染，使用率最高的3类药物为中成药、抗菌药及解热镇痛药。研究人群B级药物的使用率最高，占51.3%；有8.4%的患者使用了X级药物。完成随访151例，失访率15.6%，药师给予的药物风险评估建议患者接受率为95.4%，98.7%的患者认为妊娠咨询门诊对其有帮助且能有效缓解焦虑。结论 妊娠期药物咨询门诊能向患者提供科学的、个性化的用药指导和科普宣教，在缓解孕产妇焦虑、抑郁的方面也有显著效果。     

Interpreting population pharmacokinetic-pharmacodynamic analyses - a clinical viewpoint

The population analysis approach is an important tool for clinical pharmacology in aiding the dose individualization of medicines. However, due to their statistical complexity the clinical utility of population analyses is often overlooked. One of the key reasons to conduct a population analysis is to investigate the potential benefits of individualization of drug dosing based on patient characteristics (termed covariate identification). The purpose of this review is to provide a tool to interpret and extract information from publications that describe population analysis. The target audience is those readers who are aware of population analyses but have not conducted the technical aspects of an analysis themselves. Initially we introduce the general framework of population analysis and work through a simple example with visual plots. We then follow-up with specific details on how to interpret population analyses for the purpose of identifying covariates and how to interpret their likely importance for dose individualization.     

Drug interactions with herbal medicines

The use of herbal medicines (HM) is on the rise among the global population. Although the safety profile of many herbal medicines is promising, accumulated data show evidence of significant interactions with medications, which can place individual patients at great risk. A range of electronic databases have been reviewed for articles published in this field: Medline, Allied and Complementary Medicine Database, HealthSTAR, AMBASE, CINHAL, Cochrane Library, as well as Internet documents and manually searched references in medical journals. In this review, we examined the literature from 1966 to 2006 and focused on the importance of the risk of drug interactions and potential side effects when HM are involved. We discuss these in light of the documented findings. A review of the problematic issues is given and recommendations are made in order to encourage the setting up of clinical trials on HM and herb-drug interactions.     

Developing paediatric medicines: identifying the needs and recognizing the challenges

There is a significant need for research and development into paediatric medicines. Only a small fraction of the drugs marketed and utilized as therapeutic agents in children have been clinically evaluated. The majority of marketed drugs are either not labelled, or inadequately labelled, for use in paediatric patients. The absence of suitable medicines or critical safety and efficacy information poses significant risks to a particularly vulnerable patient population. However, there are many challenges associated with developing medicines for the paediatric population and this review paper is intended to highlight these. The paediatric population is made up of a wide range of individuals of substantially varied physical size, weight and stage of physiological development. Experimentation on children is considered by many to be unethical, resulting in difficulties in obtaining critical safety data. Clinical trials are subject to detailed scrutiny by the various regulatory bodies who have recently recognized the need for pharmaceutical companies to invest in paediatric medicines. The costs associated with paediatric product development could result in poor or negative return on investment and so incentives have been proposed by the EU and US regulatory bodies. Additionally, some commonly used excipients may be unsuitable for use in children; and some dosage forms may be undesirable to the paediatric population.     

Cardiovascular safety of non-steroidal anti-inflammatory drugs among healthy individuals

Importance of the field: Studies have raised concern on the cardiovascular safety of NSAIDs. We studied safety of NSAID therapy in a nationwide cohort of healthy individuals.

Areas covered in this review: This is a review of the literature regarding cardiovascular safety of NSAIDs with special focus on the few studies investigating healthy individuals.

What the reader will gain: Due to a high frequency of gastrointestinal complications related to NSAID treatment a new generation of NSAID, called the selective COX-2 inhibitors, were developed in order to use the beneficial pain-relieving effect of NSAIDs without the COX-1 related risk of gastrointestinal bleeding. However, the selective COX-2 inhibitor rofecoxib was withdrawn from the market in 2004 after studies had documented an increased risk of myocardial infarction related to this drug. Focus also turned to the traditional NSAIDs and found similar results for some of the older drugs, especially diclofenac and high-dose ibuprofen. Most interventional studies have not been designed specifically to evaluate the cardiovascular safety of NSAIDs and no studies have previously investigated the relationship between NSAID treatment and cardiovascular risk in healthy individuals. Overall, evidence regarding the selective COX-2 inhibitors' cardiovascular risk profile (mostly thrombo-embolic events) is derived from the clinical trials whereas results on the traditional NSAIDs are based on observational studies and meta-analyses. Importantly, some of the randomized trials comparing COX-2 inhibitors with traditional NSAIDs did not show a difference in cardiovascular risk and it cannot be denied that the traditional NSAIDs are characterized by a different cardiovascular risk-profile than the COX-2 inhibitors. A recent cohort study among one million healthy people showed that the selective COX-2 inhibitors as well as diclofenac are associated with an increased risk of death or myocardial infarction. This was further underlined by a dose-response relationship.

Take home message: Individual NSAIDs have different cardiovascular safety that needs to be considered when choosing appropriate treatment. In particular, rofecoxib and diclofenac were associated with increased cardiovascular mortality and morbidity and should be used with caution in most individuals. This notion is also valid for healthy individuals and underlines the importance of critical use of NSAID therapy in the general population and also that over-the-counter retail of NSAIDs should be reassessed.     

Design and development of a mobile app of drug information for people with visual impairment

BackgroundPeople with visual impairment presents difficulties to access the labels information of medicines. In this sense, technological tools can contribute to improve access to this information and the appropriate use of medicines in this population. However, currently, in Colombia, there are no tools to facilitate this process.ObjectiveTo design and development of a mobile app of drug information for people with visual impairment, which allows them to access information for the appropriate use of medicines.MethodsA user-centered design process is carried out in four phases was used: a) Identification the needs and barriers for appropriate use of medicines; b) Lifting of requirements, c) Interface design and prototyping, and development of the mobile app, and d) Usability test.ResultsThe study involved 48 people with visual disability, of which 69% required assistance for the use of medicines. The main barriers identified were access to information and dosing. A total of ten user requirements were identified, based on these and international accessibility standards FarmaceuticApp was designed and developed, incorporating the problems that were identified in the usability test.ConclusionA mobile app of drug information for people with visual impairment using a user-centered design process was designed and developed, highlighting the importance of involving the users and other stakeholders in the design and development m-health technologies. FarmaceuticApp could contribute to the appropriate use of medicines and improve therapeutic adherence, as well as autonomy and independence in people with visual impairment.