Fluoroquinolones Adverse reactions during clinical trials and postmarketing surveillance

The knowledge of side effects of fluoroquinolones during clinical trials and postmarketing surveillance is reviewed. Gastro-intestinal side effects (observed in 3–6% of the patients) are the most frequently observed side effects followed by side effects of the central nervous system (0.5–1.5%) and skin reactions (0.5–2%). The incidence of severe side effects is very low and most effects can be reserved rapidly upon discontinuation of therapy. Reactions of the central nervous system (sometimes severe) were the most often spontaneously reported events during the postmarketing surveillance of ofloxacin. The incidence of adverse reactions is usually in the same range as that of other antimicrobial agents like the third generation cephalosporins, imipenem and aztreonam. Fluoroquinolones are usually well-tolerated and safe drugs, but more data is needed on the long-term safety of quinolones, the safety in children, in elderly people and in severely ill patients.     

某住院药房抗感染药物使用情况分析

目的 分析住院药房抗感染药物的使用情况,为临床合理应用抗感染药提供参考.方法 根据＂药局库存管理程序＂的原始数据资料,按金额、限定日剂量进行排序、分析.结果 抗感染药物使用比例从11月份后有所下降,使用金额最大的品种依次是注射用头孢米诺钠、注射用哌拉西林钠舒巴坦钠、头孢唑啉钠针,用药频率最高的是哌拉西林钠舒巴坦钠针、头孢米诺钠针、青霉素钠针.结论 抗感染用药情况整体趋稳,β-内酰胺类、喹诺酮类是临床抗感染治疗的主导药物,个别使用频率较高的品种占用金额上升,说明在抗菌药物的使用上仍有待规范.     

The role of pharmacists in the recruitment of a cohort for postmarketing surveillance

In October 1990, a recall procedure was issued regarding the drug acitretin. The recommended post-therapy contraception period after acitretin therapy was extended from 2 months to 2 years. For a postmarketing surveillance study, we recruited a cohort from the source population of women aged 15–45 years who were exposed to acitretin. Recruitment occurred through dermatologists, and pharmacists plus dispensing general practitioners. We describe the speed of and the response to the recruitment procedures, and the representativeness of the recruited cohort. We also studied whether the individuals who gave informed consent would have preferred to be recruited by either dermatologists or pharmacists, and whether the information obtained from pharmacists and dispensing general practitioners was valid. This study revealed that pharmacists and dispensing general practitioners (drug dispensers) recruited their subjects rapidly, with no or little selection; they attained a 42% response. Dermatologists recruited their subjects slowly and selectively; they attained a 24% response. The majority of women (60%) recruited by dermatologists would have given their informed consent if they would have been recruited by their pharmacists. Drug dispensers are essential contributors to the recruitment of a study population. We do advise that such recruitment for a postmarketing surveillance study occurs by means of a collaboration between pharmacists and physicians.     

Public health problems and the rapid estimation of the size of the population at risk

Recently, the use of astemizole and terfenadine, both non-sedating H₁-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H₁-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.     

An overview of pharmacoepidemiology

Pharmacoepidemiology is the application of epidemiological principles and methods to the study of drug effects in human populations. The goal of this discipline is to characterize, control and predict the effects and uses of pharmacological treatment modalities.Pharmacoepidemiology is also concerned with the economic impact and health benefits of unintended drug effects. The increasing importance of pharmacoepidemiology has been created by the need to develop a more accurate portrait of how drugs are used in the general population. Sophisticated and potent drug carefully controlled clinical trials of Phases I, II and III. Case-control and cohort studies, which allow scientists to evaluate the effects of patient variables on clinical outcomes, provide a wealth of information regarding the study of unexpected drug effects, drug utilization, treatment costs and the individualization of therapy.     

某院中药注射剂的临床应用分析

目的 调查分析深圳市第四人民医院中药注射剂的临床使用情况,为临床更合理应用该类药物提供参考.方法 对该院2011年中药注射剂的销售金额、用药频度及2012年1-3月使用中药注射荆的住院患者的病历进行回顾性分析.另外,对其所用的中药注射剂说明书进行规范化统计.结果 该院2011年中药注射剂销售金额逐季增长,单品销售金额排序每季度有所不同,但排位变化不大.2012年1-3月中药注射剂合理使用率为74.39％.结论 该院中药注射剂销售金额所占比重较小,销售金额与用药频率同步性欠佳.中药注射剂总体使用情况较为合理,主要用于改善微循环及提高免疫力.其说明书还可以进一步完善.     

Clinical perspectives in drug safety and adverse drug reactions

Adverse drug reactions (ADRs) remain a common clinical problem since they can mimic many diseases and cause significant morbidity and mortality. Judicious prescribing is important to minimize their occurrence. Apart from the recent identification of a few pharmacogenomic biomarkers for serious reactions, many remain unpredictable. Spontaneous reporting continues to play an important role in pharmacovigilance and the value of astute clinical observation and well-documented reports of suspicions of a causal link cannot be underestimated. Many national reporting schemes have developed considerable experience and expertise over many years and have large ADR databases, which are national assets. Despite advances in pharmacovigilance, numerous deficiencies have been identified; postmarketing surveillance remains the weakest link in the regulatory process. Regulatory authorities have tended to act later rather than sooner in response to safety signals, and this, when combined with under-reporting, may have led to exposure of a large number of patients to drug-related harm before restriction or withdrawal. In an attempt to improve vigilance, international surveillance may benefit by moving from its current passive/reactive mode toward active surveillance systems with a prospective, comprehensive and systematic approach to monitoring, collecting, analyzing and reporting data on ADRs. This will include increased pressure on pharmaceutical companies to conduct postmarketing studies. Such an active/proactive approach, while maintaining focus on ADR detection, could also aim to extend knowledge of safety, such that emerging changes in risk–benefit during a drug’s marketed life are effectively communicated to clinicians and patients. Drug safety monitoring and its regulation are now undergoing an overhaul and it is hoped that vigilance, public safety and trust will improve as a result.     

The DoTS classification is a useful way to classify adverse drug reactions: a preliminary study in hospitalized patients

Objective The aim was to determine the prevalence of adverse drug reactions (ADRs) in hospitalized patients in a university hospital. Methods ADRs were identified by two evaluators, who reviewed the clinical histories of all patients admitted between 24 April and 24 May 2006. Patients with suspected ADRs were contacted. Three different investigators evaluated causality, the degree of preventability, and the mechanism producing the ADR. Causality was assessed using the scale proposed by the World Health Organization (WHO), and preventability was assessed using the modified Schumock and Thornton criteria. Key findings There were 32 ADRs in 104 hospitalized patients. Effects on the autonomic nervous system were the most common (13%) and the drugs most frequently implicated were systemic antimicrobial drugs (19%). Fifty‐four per cent of the ADRs were classified as possible. Using the Dose, Time and Susceptibility (DoTS) classification, 77% of the ADRs were classified as being of collateral dose‐responsiveness (i.e. they occurred within the range of therapeutic doses), and 65% were classified as intermediate reactions. The susceptibility factors associated most frequently with ADRs were comorbidities (i.e. the presence of diseases that were considered as risk factors to developing an ADR; 36%), age (26%) and exogenous factors (i.e. the presence of drug interactions that were involved in the occurrence of ADRs; 17%). Fifty per cent of the ADRs could have been prevented. Conclusions ADRs are very frequent in hospitalized patients and a significant proportion of them is preventable. The DoTS classification allowed complete evaluation of the types of ADR encountered. We are currently carrying out a much larger prospective study.     

Place of quinolones in the therapeutic armoury

On the basis of antimicrobial activity, resistance development, pharmacokinetics, side effects and pre-clinical results, the applicability of the quinolones ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin is assessed. These quinolones seem especially useful in infections in hospitalized patients, in gonococcal infections and in urinary tract infections. Also salmonellosis and shigellosis might be indications for quinolones.     

Retrospective analysis of drug treatment in epileptic patients

An epidemiological analysis was performed of the adult, out-patient epilepsy clinic population of a university hospital during the period from 1 January 1981 through 30 June 1985. The number of patients that could be traced amounted to 590. An at random sample of 207 were retrospectively analysed. Gender distribution was male:female = 1.46. The mean age was 37.4 years. The diagnoses were classified according to the classification of the International League Against Epilepsy (ILAE). A preponderance of partial seizures was present, reflecting the selection in a university out-patient clinic of more difficult to treat forms of epilepsy. Antiepileptic drugs used in the treatment varied; monotherapy was obtained in 46% of the cases and carbamazepine was the most frequently prescribed drug (49%). Changes in seizure severity and factors associated with epilepsy are described. A discrepancy was found between the suspected drug levels, based upon the physician's judgement, and the plasma level measured in those patients in whom drug levels were monitored; factors interfering with clinical judgement are discussed.     

Proportion of osteoporotic post‐menopausal women at increased risk for upper GI adverse events associated with bisphosphonate therapy

Background — The bisphosphonate alendronate has been associated with higher rates of adverse oesophageal effects when used in the community setting compared to what was observed in the clinical trials. Patients with a history of gastroesophageal problems or who are concurrently using an NSAID therapy may be at increased risk for the gastroesophageal problems associated with alendronate use. This study assesses the proportion of post‐menopausal women in the community with osteoporosis that are at increased risk for gastroesophageal adverse effects associated with alendronate. Methods — The administrative database for the Quebec government drug benefit program was used to identify a cohort of 5400 post menopausal women aged 65 years or older who were using the bisphosphonate etidronate for the treatment of osteoporosis. Patients were evaluated for the presence of either risk factor, chronic GI drug therapy use (a marker for prior gastroesophageal problems) or chronic NSAID use. Findings — 31% of women taking etidronate were also chronically using GI drug therapies and 50% were using NSAIDs; 18% of the women were using all three drugs. Interpretation — Many osteoporosis patients in the community setting who are candidates for bisphosphonate therapy might be considered at increased risk for alendronate's gastroesophageal adverse effects. This may account for differences in pre‐marketing and postmarketing event rates. Copyright © 2000 John Wiley & Sons, Ltd.     

Long-term safety experience with bendamustine for injection in a real-world setting

Background: Bendamustine hydrochloride (bendamustine) was approved for first-line treatment of patients with chronic lymphocytic leukemia (CLL) and relapsed indolent B-cell non-Hodgkin’s lymphoma (NHL). Pharmacovigilance data have been collected since bendamustine’s approval to enhance understanding of its long-term safety profile. Here we provide an overview of the pharmacovigilance data for bendamustine that have led to label updates related to safety and administration since its approval.

Research design and methods: Adverse events (AEs) captured from 12 quarterly postmarketing periodic adverse drug experience reports spanning 2008–2015 were included and summarized. AEs were classified as serious or nonserious and expected or unexpected.

Results: Adverse events that resulted in label updates included Stevens-Johnson syndrome, toxic epidermal necrolysis, extravasation, secondary neoplasm, and drug reactions with eosinophilia and systemic symptoms. Preventive measures for tumor lysis syndrome were revised. Although this review may be limited by voluntary reporting, the adverse events reported for bendamustine in a large, heterogeneous population with a long follow-up relative to recently approved treatments provide a much broader understanding of its safety profile.

Conclusions: Based on these observational data, bendamustine appears to have a favorable risk-benefit profile and remains a useful option when considering a management strategy in patients with CLL and NHL.     

Evaluation of a patient event report monitoring system

Background — Detection of adverse drug reactions needs improving. Consumer recruitment and reporting is controversial. Aim — Pilot a method of adverse drug event reporting by patients. Methods — Patients commencing on long‐term medications were asked to record adverse events in a diary for 8 months. Three methods of recruiting patients were compared, through community pharmacies by a pharmacist or a research nurse and by a clinical pharmacist in a teaching hospital. Results — 119 subjects: 77 recruited by community pharmacists, 20 by a research nurse located in community pharmacies and 22 by a clinical pharmacist. Refusal rates were 57.2, 78.0 and 53.2% respectively. Nineteen (16.0%) people withdrew and nine (7.6%) people were lost to follow‐up. Thirty (33.0%) people experienced an adverse event attributed to the medication they were taking. Conclusion — Evaluation of this patient event reporting monitoring system showed that patients can be recruited by pharmacists in community and hospital settings. Refusal rates were smaller when the community pharmacist was recruiting compared to the research nurse. Patients are capable of recording adverse medical events, particularly those that result in doctor visits or hospitalization. Copyright © 2000 John Wiley & Sons, Ltd.     

Surveillance of adverse effects during a vaccination campaign against meningitis C

Objective To describe adverse events occurring after mass vaccination with conjugate and nonconjugate vaccines and to assess the incidence of serious adverse effects. Methods A mass immunisation campaign against meningococcal C disease was conducted in two French administrative areas, Landes and Pyrénées atlantiques, for 2 months (from October to December 2002). Adverse events were reported by families and physicians by means of a specific reporting form returned to the pharmacovigilance centre 15 days after vaccination. Results The target population was 260,630 individuals aged between 2 months and 24 years. About 179,000 children and young adults were vaccinated. A total of 92,711 report forms were received by the pharmacovigilance centre, and 12,695 subjects presented at least one adverse event. The most frequently involved systems/disorders were application site disorders (48.4%), whole-body general disorders (21.8%), central and peripheral nervous system disorders (14.6%), and gastrointestinal system disorders (4.7%). Most of these adverse events were transient and not serious. There were 13 serious adverse events: one each of syncope, fever, headache with fever, neuralgia, serum sickness, arthritis, purpura, facial paralysis, multiple sclerosis, lipoma, and meningism, and two cases of bronchospasm. No significant difference was found in rates of adverse event reports between both vaccines. The estimated incidence of serious adverse effect reports was 7 per 100,000. Conclusions This campaign was the second immunisation campaign undertaken in France involving both physicians and families as reporters. Although unlabeled adverse effects were identified during this campaign, they were mostly nonserious and have been known to occur with other vaccines.