A systematic review on the application of pharmaco­epidemiology in assessing prescription drug-related adverse events in pediatrics

ABSTRACT

Objectives: To conduct a systematic review of recent case-control and cohort studies in assessing adverse drug events (ADEs) among pediatric patients aged between 0 and 18 years; to establish strengths and limitations of pharmacoepidemiology when applied in evaluating pediatric drug safety; and to identify areas of pediatric drug safety that may be suitable for future pharmaco­epidemiological investigations.

Methods: A PubMed search was conducted using a list of keywords representing drugs, adverse drug events, case control and cohort studies, and pediatric population. Selection criteria were used to extract relevant studies published from 1/1 2000 to 7/1 2006.

Results: Twenty-seven studies met our criteria. Of them, 12 used a prospective cohort design. The others were either case-control (seven) or retrospective cohort (eight) studies, based on the analysis of existing data­bases. More than half of the studies included more than 500 subjects. Inclusion and exclusion criteria for participants in these studies were generally not very stringent. The subjects closely resembled patients in the real-world settings. The length of study follow-up ranged from 1 day to 40 years. In eight studies, the length of follow-up surpassed 5 years. Potential confounding factors were taken into consideration in all of the studies. But the database-based studies generally failed to control for some important clinical variables such as disease severity. Misclassification of drug exposures also occurred in some of these studies.

Conclusions: Despite some limitations, pharmaco­epidemiology proves to be useful for assessing ADEs in pediatrics. With appropriate study design, this method­ology can bolster our understanding about the safety of pediatric drug use. Several areas of pediatric drug safety may especially be suitable for future pharmacoepidemi­ological investigations. These areas include the safety of polypharmacy, long-term drug effects, and off-label drug use.     

Monitoring medicines use: the role of the clinical pharmacologist

Appreciation of the potential of newly marketed medicines to produce both benefit and harm has increased the role of the clinical pharmacologist. Pharmacoepidemiology applies epidemiological reasoning, methods and knowledge to the study of the uses and effects of drugs in human populations. Pharmacovigilence identifies and then responds to safety issues about marketed drugs. Whilst adverse drug reaction (ADR) reporting systems can identify potential problems with drugs, determination of causation requires population-based studies of adverse events (including information from large clinical trials), which attempt to link unequivocally the adverse outcome to the drug in question. Pharmacovigilance is closely linked to postmarketing surveillance and is important for determining issues such as the long-term effects of drugs, identification of low-frequency ADRs, the effectiveness of drugs for their licensed indications or in new indications and other factors which may modify the efficacy and effectiveness of the drug in question. The related field of drug utilization developed in parallel with the study of adverse drug reactions, in recognition of the dramatic increase in the marketing of new drugs, the wide variations in the patterns and extent of drug prescribing, the growing concern about ADRs and the increasing costs of drugs. With the ever increasing number of recognized adverse effects of drugs, prescribing errors, patients' expectations concerning drug safety and the need for appropriate new drug appraisal, the clinical pharmacologist will play an important role both in the introduction of new drugs and in improving the safe and effective use of established drugs.     

Formulation approaches to pediatric oral drug delivery: benefits and limitations of current platforms

Introduction: Most conventional drug delivery systems are not acceptable for pediatric patients as they differ in their developmental status and dosing requirements from other subsets of the population. Technology platforms are required to aid the development of age-appropriate medicines to maximize patient acceptability while maintaining safety, efficacy, accessibility and affordability.

Areas covered: The current approaches and novel developments in the field of age-appropriate drug delivery for pediatric patients are critically discussed including patient-centric formulations, administration devices and packaging systems.

Expert opinion: Despite the incentives provided by recent regulatory modifications and the efforts of formulation scientists, there is still a need for implementation of pharmaceutical technologies that enable the manufacture of licensed age-appropriate formulations. Harmonization of endeavors from regulators, industry and academia by sharing learning associated with data obtained from pediatric investigation plans, product development pathways and scientific projects would be the way forward to speed up bench-to-market age appropriate formulation development. A collaborative approach will benefit not only pediatrics, but other patient populations such as geriatrics would also benefit from an accelerated patient-centric approach to drug delivery.     

The safety of novel drugs used to treat irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder with a high prevalence. Besides efficacy, the safety of each drugs used to treat GI disorders is an important issue in the drug development process.

Areas covered: This article reviews all Phase I to IV clinical trials or case reports with results related to the safety of novel GI drugs. The drugs are currently approved or under evaluation for approval.

Expert opinion: Most of the reported adverse events were related to the GI tract with mild-to-moderate severity. Diarrhea was significantly higher versus placebo following use of linaclotide and renzapride, similar to that of constipation with ramosetron. Lubiprostone, linaclotide and rifaximin with low systemic bioavailability have less adverse events and exert more advantageous results. Asimadoline acts peripherally on κ-opioid receptors and is not associated with CNS side effects. As lubiprostone and linaclotide cause dose-dependent adverse events, starting the treatment with the lowest effective doses is advised. Ramosetron is under evaluation for diarrhea-predominant IBS due to its acceptable safety and tolerability, besides its efficacy. Rifaximin, asimadoline and renzapride are still in need of more long-term studies regarding their safety.     

儿科门诊输液处方合理性调查

目的：评价医院儿科门诊输液处方的合理性,促进儿科合理用药。方法随机抽查医院2013年6月输液药房中儿科门诊输液处方500张,对联合用药处方、应用糖皮质激素的处方和不合理用药处方进行分类和统计分析。结果联合用药处方、应用激素处方、不合理用药处方分别占调查处方的91.6％、28.2％、2.6％。不合理用药情况有：药物选择不合理、用量不合理、溶媒选择不合理、联合用药不合理等。结论进行儿科门诊输液处方不合理用药调查,将信息及时反馈给医师,护士,可减少不良反应的发生。有助于加强医师、药师、护士合作,促进儿科合理用药。     

Impact of medication therapy management on pharmacotherapy safety in an intensive care unit

Background Drug-related problems are mostly preventable or predictable circumstances that may impact on health outcomes. Clinical pharmacy activities such as medication therapy management can identify and solve these problems, with potential to improve medication safety and effectiveness. Objective To evaluate ability of medication therapy management service to detect drug-related problems and prevent adverse drug events. This study also aimed to assess the risk factors for drugrelated problem occurrence. Setting Medical intensive care unit of a public tertiary hospital in Brazil. Methods Patients were evaluated by a clinical pharmacist, who provided medication therapy management service. Detected drug-related problems were categorized according to the Pharmaceutical Care Network Europe methodology and analyzed in multinomial regression to identify risk factors. Main outcome measure Potential risk factors for drug-related problem occurrence. Results The proposed medication therapy management service allowed detection of 170 drug-related problems that had potential to reach patients causing harm and other 50 unavoidable adverse events. Drug-related problems identified were more often associated with antibacterial use, caused by improper combinations or inadequate drug dosage. These problems required interventions that were accepted by the multidisciplinary team, resulting in more than 85% adherence and total problem solving. Main risk factors identified were previous diagnosis of kidney injury (OR?=?8.38), use of midazolam (OR?=?7.96), furosemide (OR?=?5.87) and vancomycin (OR?=?4.82). Conclusion Medication therapy management proved to be an effective method not only for drug-related problem detection, but also for adverse drug event prevention, contributing to improve patient safety.

     

Safety and efficacy of treatment for chronic hepatitis C with a focus on pegylated interferons: the backbone of therapy today and in the future

Introduction: Approximately 170 million people are infected with HCV. The efficacy of treatment for chronic hepatitis C has increased markedly over the last 2 decades. Optimal patient management requires thorough knowledge of the adverse effect profiles of drugs used for this condition and strategies to mitigate these effects.

Areas covered: The efficacy, safety and tolerability data associated with IFN-based therapy, with particular attention given to the two licensed pegylated IFNs (peg-IFNs), are identified by focused searches of Medline. Recommendations for the management of adverse events are also given. Focused searches of PubMed are done using the terms peginterferon and chronic hepatitis C. The results of large randomized clinical trials are emphasized.

Expert opinion: Patients receiving treatment with peg-IFN plus ribavirin for chronic hepatitis C must be monitored closely for adverse events. These events can be effectively managed to maximize patients' adherence and thus the chance of treatment success. Direct-acting antiviral agents are expected to be approved in the near future and will be used in select patients with a peg-IFN plus ribavirin ‘backbone’.     

Clinical safety of tocilizumab in rheumatoid arthritis

Importance of the field: Tocilizumab is a new biologic disease-modifying antirheumatic drug directed against the activity of IL-6, a key pro-inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA). This drug has proved highly effective in RA patients, including those who had previously not responded to anti-TNFs. As side effects are a major cause for discontinuing biologic therapy, the present article focuses on the tolerability profile of tocilizumab.

Areas covered in this review: This review describes the adverse events (AEs) reported in RA patients treated with tocilizumab. Most data are derived from controlled clinical trials and their open-label extensions.

What the reader will gain: The reader will gain a comprehensive review of treatment-emergent AEs associated with tocilizumab therapy. These AEs include infections, including opportunistic infections, infusion and hyper-sensitivity reactions, gastrointestinal perforation, and laboratory test abnormalities, especially hepatic transaminase elevations, altered lipid profile and neutropenia.

Take home message: Based on current data, tocilizumab appears to have an acceptable safety profile inasmuch as most AEs were manageable or controllable. However, results from large scale pharmacoepidemiological investigations and appropriate post-marketing surveillance are awaited to identify the full spectrum of AEs and define the true benefit:risk ratio of tocilizumab.     

Pharmacokinetic and clinical studies on teicoplanin for sepsis by methicillin-cephem resistant Staphylococcus aureus in the pediatric and neonate field

Pharmacokinetics, clinical efficacy and safety of teicoplanin (TEIC) were evaluated in pediatric and neonate patients with MRSA sepsis in the dosages approved in overseas. The administrated dose for pediatrics patients was 10 mg/kg once at hour 0, 12 and 24, followed by every 24 hours intervals. In neonates patients, first dose was 16 mg/kg, then 8 mg/kg every 24 hours intervals. 1. Pharmacokinetic results. All 17 patients (9 neonates and 8 pediatrics) who received TEIC were evaluated for pharmacokinetics. Trough concentrations were analyzed in 16 patients (9 neonates and 7 pediatrics) excluding one patient for lack of measurement of drug concentration at day 7. No patient with a concentration exceeding 60 micrograms/mL in peak or trough concentrations were reported. Mean concentrations in trough at day 3, 4 and 7 in neonates were 15.2, 14.7 and 17.8 micrograms/mL, and in pediatrics were 12.5, 12.2 and 13.1 micrograms/mL, respectively. These results were similar to those reported in foreign pediatrics and neonates patients. 2. Efficacy and safety results. Since no patient was excluded, all patients were evaluated for efficacy and safety. Microbiological efficacy as well as clinical cure were secondarily evaluated in 2 patients for whom MRSA was isolated from blood. Clinical efficacy rate was 76.5% (13/17) and number of cases in judgments of excellent, good, fairly improved and no change were 12, 1, 3 and 1 cases respectively. The patients for whom MRSA was isolated from blood were judged as MRSA eradicated case and cured without any additional anti-MRSA drugs. Adverse events were reported in 2 neonates and 3 pediatric patients. Possibly related adverse events to study drug (adverse drug reactions) were: 1 case of respiratory disorder, thrombocythemia, gamma-GTP increased, GOT increased and GPT increased in 3 pediatrics. These results suggest that an application of overseas dose regimen of TEIC for neonate and pediatrics is appropriate in Japan.     

Impact of SLCO1B1 (OATP1B1) and ABCG2 (BCRP) genetic polymorphisms and inhibition on LDL-C lowering and myopathy of statins

1. Statins are the preferred class of drugs for treating patients with atherosclerosis and related coronary heart disease. Treatment with statins leads to significant low-density lipoprotein cholesterol (LDL-C) lowering, resulting in reductions in major coronary and vascular events. Statins are generally well tolerated and safe; however, their use is complicated by infrequent, but often serious, muscular adverse events.

2. For many statins, both efficacy and risk of adverse muscle events can be influenced by membrane transporters, which are important determinants of statin disposition. Genetic polymorphisms and drug–drug interactions (DDIs) involving organic anion-transporting polypeptide 1B1 and breast cancer resistance protein have shown the capacity to reduce the activity of these transporters, resulting in changes in LDL-C lowering by statins, as well as changes in the frequency of adverse muscle events associated with their use.

3. This review presents evidence for how reduced transporter activity impacts the safety and pharmacology of statins. It expands on the scope of other recent statin reviews by providing recommendations on in vitro evaluation of statin interaction potential, discussing how reduced transporter activity impacts statin management during drug development, and proposing ideas on how to evaluate the impact of DDI on statin efficacy during clinical trials. Furthermore, the potential clinical consequences of perturbing statin efficacy via DDI are discussed.

     

某三甲医院门诊与住院患儿用药结构特点与差异及合理性分析

目的：通过对某三甲医院儿科使用的抗菌药物、呼吸系统药物和消化系统药物现状的抽样调查,对比门诊与住院患儿用药特点与差异并进行相关因素分析,以期促进儿科用药的合理性与安全性。方法：随机抽取某院儿科2011年2月至2012年9月门诊处方2400张和2010年6月至2012年5月儿科住院电子病历1600份,采用DDDs排序法对数据进行统计分析。结果：门诊与住院患儿在给药途径、给药剂量、给药剂型以及药品种类选择上存在一定的差异。给药途径门诊患儿以口服为主,住院患儿以静脉滴注为主;部分呼吸系统药物用药剂量过大,住院患儿抗菌药物的使用起点选择较高,使用率、联合用药率也较高。结论：虽然该院儿科用药结构基本合理,但调查结果显示静脉给药方式在儿童用药中已逐步成为主流,为保证其用药的安全性,抗菌药物的合理选用（或联用）以及儿童用药剂量科学规范化值得重视与研讨。     

Sumatriptan therapy for headache and acute myocardial infarction

Importance of the field: Migraine is a common, debilitating, chronic neurovascular disorder. Triptans are considered the drugs of choice to treat migraine attacks; however, their use is limited owing to concerns about cardiovascular safety.

Areas covered in this review: The aim of this review is to describe: the mechanisms of action of triptans; the case-reports of acute myocardial infarction (AMI) associated with sumatriptan use; and the results of studies evaluating its tolerability and safety.

What the reader will gain: Sumatriptan administration can be followed, in close temporal relationship, by AMI in young or adult migraine patients. Some of these cases have developed in subjects taking their first dose. Based on the results of prospective studies, the risk of severe cardiovascular adverse events after the use of a triptan is estimated at 1:100,000 treated attacks. These adverse events, albeit very infrequent, highlight the importance of careful adherence to the sumatriptan prescribing information.

Take home message: Inherent in its mechanism of action, sumatriptan could produce (coronary) vasospasm sometimes followed by AMI. The drug should not be prescribed to patients with history, symptoms or signs of ischemic vascular disease; an in-depth evaluation should be carried out in subjects at intermediate cardiovascular risk.     

某院2018年1月—6月儿科门诊处方点评和用药合理性分析

目的:分析医院2018年1月—6月儿科门诊用药情况,为儿科患者临床合理用药提供参考。方法:采用人工随机抽签法抽取医院2018年1月—6月儿科门诊处方1243张,统计其患者的信息、用药品种数和抗菌药物、注射剂、静脉输液、基本药物等使用情况;分析其处方用药合理性及不合理用药的原因。结果:儿科门诊1243张处方中,每张处方平均用药品种数为(3.05±0.69)种,每张处方使用基本药物平均数为(1.35±0.45)种,基本药物使用率为45.21%;不合理用药处方29张为2.33%,抗菌药物使用率为46.74%。结论:儿科患者用药存在一定的不规范现象,主要问题在于适应证不适宜用药,应加强硬件建设,为合理用药提供基础设备,加强其合理用药规范管理,以确保儿童用药的安全性和有效性。     

Adverse reactions to β-lactam antimicrobials

Introduction: Beta-lactam antibiotics are among the most clinically useful antimicrobials used in medicine. Unfortunately, adverse events related to their use remain poorly understood by many clinicians and, in particular, the misdiagnosis of β-lactam allergy and misunderstanding of crossreactivity among members of the β-lactam antibiotics may effectively eliminate a whole class of antimicrobials from use and require the use of broader spectrum agents with less well-established safety profiles.

Areas covered: This review describes the range, diagnosis and management of adverse events associated with β-lactam antimicrobials, particularly focusing on recognition, diagnosis and management of true allergy and risk of cross-sensitivity between β-lactam antibiotics. A literature review was undertaken using PubMed, focusing primarily on literature published in the past 10 years relating to β-lactam adverse events and allergy.

Expert opinion: Beta-lactams are generally safe drugs and serious adverse events are rare and allergy is overdiagnosed. Accurate diagnosis can usually be achieved through careful history and in some instances skin or in vitro testing is required. Even among individuals with true immediate-type allergy to penicillin, most cephalosporins are readily tolerated and desensitization is usually an option in cases where no alternate antimicrobials are available. Other allergic reactions (Type II, III and IV) are rare and avoidance of the culprit agent is generally recommended. Nonallergic or morbilliform rashes are generally not allergic in nature and should not prompt drug or class avoidance. Other adverse events are frequently dose-related and can be avoided by appropriate dosing and consideration of renal function.     

Synthetic investigational new drugs for the treatment of tuberculosis

Introduction: Tuberculosis (TB) is a major global health concern. And while there are treatments already on the market, there is a demand for new drugs that are effective and safe against Mycobacterium tuberculosis, which reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multidrug-resistant TB (MDR-TB).

Area covered: This review covers promising novel investigational TB drugs that are currently under development. Specifically, the authors review the efficacy of novel agents for the treatment of TB in preclinical, phase I and phase II clinical trials. The authors also review the safety and tolerability profiles of these drugs.

Expert opinion: Bedaquiline and delamanid are the most promising novel drugs for the treatment of MDR-TB, each having high efficacy and tolerability. However, the best regimen for achieving better outcomes and reducing adverse drug reactions remains to be determined, with safety concerns regarding cardiac events due to QT prolongation still to be addressed. Pretomanid is a novel drug that potentially shortens the duration of treatment in both drug-susceptible and drug-resistant TB in combination with moxifloxacin and pyrazinamide. Linezolid shows marked efficacy in the treatment of MDR-TB and extensively drug-resistant TB (XDR-TB), but the drug is known to cause significant adverse drug reactions, including peripheral neuropathy, optic neuropathy and myelosuppression. These adverse reactions must be considered prior to prescribing long-term usage of this drug.     

氯吡格雷在儿科中的应用进展

氯吡格雷作为新型的抗血小板药物,在儿科的用药需求日趋增多,氯吡格雷在药动学、药效学以及降低某些不良反应的发生方面较其他抗血小板药物具有优势,本文拟综述氯吡格雷机制、药理学,以及在儿科使用情况,主要包括儿科应用的疾病种类和剂量选择等,并初步探讨了基因检测对儿童氯吡格雷的指导价值,为儿科临床合理应用氯吡格雷提供依据。     

Challenges and opportunities for pharmacoepidemiology in drug-therapy decision making

Pharmacoepidemiology is a relatively new and evolving science that attempts to quantify mainly adverse drug events and patterns of drug use in a large population. The strength of pharmacoepidemiology over randomized trials is the ability to quantify rare adverse events that may occur over long periods. Recently, discordance in the results of pharmacoepidemiologic studies has made it difficult for clinicians and policy makers to make informed drug-therapy decisions. This commentary addresses the strength of pharmacoepidemiology and the advances in the methodology of pharmacoepidemiologic studies over the years. We also discuss the potential problem of discordant results and urge pharmacoepidemiologists to develop good practice guidelines for the conduct of pharmacoepidemiologic studies.