Adverse drug reactions in pulmonology

“Black box” 101: How the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk

8. Drug allergy

Many millions of dollars have been spent on preventing adverse drug reactions at the point of prescribing. Automated systems help identify drug-drug interactions and excessive drug doses. Computerized alerts warn prescribers about potentially inappropriate drugs in older adults. Yet, only one-quarter of adverse drug reactions can be prevented by catching errors or problems at the time of prescribing.1 The remainder of adverse drug reactions are not the result of prescriber error, but simply represent the known side effects of drugs. Some patients who take calcium channel blockers will develop peripheral edema. Some patients who take selective serotonin reuptake inhibitors (SSRIs) will experience marked sexual dysfunction. For some drugs, risk factors have been identified that place a patient at higher risk of developing an adverse event. However, in most cases, we cannot predict who will develop an adverse drug reaction, and who will not. We prescribe and hope for the best. Unfortunately, physicians don’t do a good job of identifying and appropriately managing adverse reactions when they do occur. Many patients don’t tell their doctors when they are experiencing an adverse event, and we often don’t ask.2–3 Moreover, physicians often misattribute the symptoms of an adverse drug reaction as the manifestation of an underlying disease, leading to diagnostic workups and a prescribing cascade of new medications rather than treating the problem at its source by stopping the offending drug.4 On a broader level, only a small fraction of adverse drug reactions are reported to the FDA Adverse Event Reporting System (http://www.fda.gov/Safety/MedWatch/), hindering efforts for post-marketing surveillance of drug safety. These problems with recognizing and managing adverse drug reactions occur not because physicians are incompetent, but because we lack the systems that would allow us to systematically identify and address medication-related problems. The research described by Forster et al. in this issue of Archives shows a promising approach to bridge this quality gap. Building on past studies that have shown the benefits of reaching out to patients to identify adverse drug reactions, the authors developed a hybrid system. Three days after a drug was newly prescribed, the system generated a phone call to the patient. Using interactive voice response technology, the system asked the patient four simple questions about problems they may be having with their drugs and whether they wanted to talk to a pharmacist. The process was repeated two weeks later. One-third of contacted patients needed a follow-up call from the pharmacist. Overall, the system identified slightly under half of the 22% of patients who experience an adverse drug reaction. In addition, it identified one-third of the 6% of patients who were non-adherent to their medications. This is exciting and highly promising. It is also not ready for widespread implementation. While the system detected a number of medication-related problems, it missed more than half of adverse drug reactions and two-thirds of episodes of non-adherence in patients - and would likely have done worse outside the controlled environment of a research setting. For most patients, the simple act of reaching out is necessary but not sufficient. People don’t develop adverse drug reactions – they develop symptoms, which may be mistakenly attributed to causes other than drugs (including “getting old”), and which they may be hesitant to disclose. (Other adverse reactions may be completely asymptomatic but nonetheless serious, such as progressive hyperkalemia or anemia). Outreach calls may also be asynchronous with when the patient develops a medication-related problem. These challenges bedevil the widespread practice of calling patients several days after hospital discharge to inquire on their wellbeing and identify problems with their medications. While a wonderful idea, relatively little is known about how well these follow-up procedures actually identify problems, and although there is some evidence that these interventions are effective, the benefits are not as great as one might hope.5 What might be most helpful is a multifocal approach, in which the surveillance strategies being developed by Forster and like-minded colleagues are coupled with efforts to educate and encourage patients to be active partners in monitoring adverse reactions and non-adherence to their medications.6 This latter approach is best exemplified by health-coach based approaches pioneered by Coleman and others, in which impressive improvements in health resulted not from bringing services to patients, but by helping patients be engaged participants in their own care. 7 These interventions are complex, and their potential benefits do not diminish the substantial contribution of surveillance-based approaches. Nonetheless, the solution to the problems of adverse drug reactions and non-adherence cannot solely rest on bringing the health care system closer to the patient. We need to empower our patients to come closer to us.

Objective To evaluate the safety of domperidone in children. Methods Clinical studies involving domperidone used in children were searched from PubMed, Embase, Cochrane Library, Chinese Biology Medical disc, CNKI, VIP, and Wanfang Database. Adverse drug reaction information bulletins which were reported by WHO Pharmaceuticals Newsletter and National Center for adverse drug reaction monitoring were searched and adverse drug reactions (ADR)/adverse drug events (ADE) related to domperidone were collected. Websites of European Medicines Agency, Food and Drug Administration of United States, Medicines and Healthcare Products Regulatory Agency (MHRA), Health Canada, and Therapeutic Goods Administration were searched and information of risks and benefits related to domperidone treatment were collected. Randomized controlled trails (RCTs) were Meta-analyzed using RevMan 5.2 software and other data were descriptively analyzed. Correlation analysis of domperidone and adverse drug reactions was performed using evaluation criteria of WHO. Severity of ADR/ADE was evaluated using criteria CTCAE 4.03 of United States Department of Health and Human Services. Results A total of 9 RCTs, 1 cohort study, 4 self-controlled studies, and 24 case reports were entered in this study. Meta-analysis of 9 RCTs showed the following results. There were no statistical significance in the incidence of ADR in children between the domperidone group and the control groups of placebo, cisapride, and mosapride. The incidence of ADR in children in the domperidone group was lower than that in the metoclopramide (RR=0.44, 95%CI: 0.23-0.86, P=0.02), and higher than that in the Traditional Chinese Medicine group (RR=16.09, 95%CI: 2.01-129.04, P=0.01). There were no serious adverse events of domperidone reported in the 9 RCTs. It was showed in the self-controlled study that oral domperidone was associated with QTc prolongation in neonates. One hundred and one cases of ADR were reported in 24 case reports. Of them, 80 cases (79.2%) of ADR were mild-to-moderate (CTCAE grading 1-2), 21 cases (20.8%) of ADR were severe (CTCAE grading 3), and no ADR with CTCAE grading 4-5 was reported. The results of causality assessment on above mentioned 101 cases of ADR showed that 2 cases of ADR were associated with domperidone certainly, 76 were probably, 15 cases of ADR induced by drug overdose, and 2 cases induced by combination use of medicines that may cause the same adverse reactions. In April 2014, European Medicines Agency suggested to limit clinical indications and dosage of domperidone. In September 2014, MHRA of Britain announced that domperidone was no longer to use as over-the-counter. Conclusions No enough evidences to prove that the incidence of ADR induced by domperidone was higher than that by the placebo, other gastro-kinetic agents, and other conventional treatments in children. The risks of serious ADR occurrence existed in children with domperidone treatment. Key words: Domperidone; Child; Safety

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Consumer reporting of adverse drug reactions: Systems that allow patients to report side effects of the drugs they are taking have yielded valuable information for improving drugs safety and health care.

The Practitioner's Role in Detection of Adverse Drug Reactions

Objective To construct the active monitoring system for adverse drug reactions based on the trigger technology and explore its application value. Methods Based on the DTHealth system and electronic medical records system, using the Brower/Server architecture, DHCMedBase2.0.doc, Ext 3.1-API Documentation technology to design the trigger of the data definition language. The monitoring group selected the adverse drug reactions which can be used to reflect with the laboratory information, 12 triggers were chosen after communicating with the clinical medical staff, the related procedures were embedded in the hospital information system, accordingly, the active monitoring system of adverse drug reaction based on the trigger technology were constructed. By the three pharmacists the full-time work, the monitoring work within 23 wards of the hospital about 800 patients were finished through the triggers of adverse drug reactions monitor, and the suspected adverse drug reactions were filtered, evaluated and reported. Results The active monitoring system of adverse drug reactions based on the trigger technology started operation in January 1st, 2014, and run until the June 30th, 2014, 561 positive patients were monitored by the triggers, and 71 adverse drug reactions which involved 28 kinds of drugs were identified, the total positive rate was 12.7%. The laboratory index of 21 patients were found to have a marked abnormality but not beyond the normal range, among them the 12 patients had to change the treatment to avoid the possible adverse drug reactions. Conclusion The application of the trigger technology successfully constructed the active monitoring system of adverse drug reactions, which can improve efficiency of the active monitoring for adverse drug reactions, at the same time, realize the early warning function. Key words: Drug-related side effects and adverse reactions; Drug monitoring; Automatic data processing

Introduction : The lack of knowledge regarding the incidence of adverse drug reactions in the hospital setting and their impact on morbidity and mortality is, nowadays, a major health problem in Angola. In the last years, notifications of adverse drug reactions have been practically null, namely at a hospital level. It is of great importance to characterize the incidence of adverse drug reactions occurring in a hospital setting, in order to implement measures towards improving the quality of healthcare services. Material and Methods: We conducted a descriptive, prospective observational study to characterize the incidence of adverse drug reactions (ADRs) in patients admitted to the Central Hospital “Josina Machel” in Luanda during the year 2014. An intensive monitoring through active search for adverse reactions possibly related with the drugs prescribed to patients was performed. Results : Of a total of 2041 hospitalized patients, 175 had adverse drug reactions. The incidence rate was 4.74% in the medicine service (n = 1077) and 12.86% in the therapy service (n = 964). A total of 209 adverse drug reactions were identified, averaging 1,2 adverse drug reactions per patient. The highest incidence rate of adverse drug reactions was recorded in patients aged between 18 and 35 years old, with 79 patients (45.14%). With regard to therapeutic class, it was found that antimicrobials were the drugs most commonly associated with adverse reactions, with 71 notifications (40.57%), followed by analgesics, antipyretics and anti-inflammatory steroids with 20,00%. Quinine and artesunate were the antimicrobials most frequently implicated in causing an adverse drug reaction, with 25 (14.29%) and 15 (8.57%) notifications respectively. In the group of anti-inflammatory drugs, diclofenac stood out with 13 notifications (7.43%). The most common clinical manifestations were skin rash, which corresponded to 23,44% of the total number of adverse drug reactions, followed by bleeding, which accounted for 8.6% of the number of adverse reactions registered (n = 18). Within the group of antimicrobials, antimalarials and cephalosporins were the drugs most commonly associated with skin lesions, with 27 notifications (55.10%). Most of adverse reactions were moderate in severity (66.86%) and were classified as probably drug-related (80.57%). Discussion and Conclusion : A high frequency of adverse drug reactions was found in hospitalized patients, particularly in the therapy service. It was evident the subnotification of adverse reactions by health professionals and the need for a system of notification of adverse reactions that combines passive and active surveillance for the prevention and detection of adverse drug reactions.

To evaluate the pattern of immunosuppressive drug adverse reactions in adult kidney transplant recipients in Iran. Adult kidney transplant outpatients under immunosuppressive therapy were recruited into the study. All adverse drug reactions to immunosuppressants and their relevant clinical and paraclinical characteristics were recorded. Causality assessment was performed by the Naranjo algorithm. The seriousness of adverse drug reactions was determined by the World Health Organization definition. The Schumock and Thornton questionnaire was used to assess the preventability of adverse drug reactions. Statistical analyses were performed. A total of 1100 adverse drug reactions were detected from 120 kidney transplant recipients. Increased appetite (9.09%) was the adverse reaction reported most frequently. Causality assessment revealed that 1019 adverse drug reactions (92.64%) were possible. Forty adverse drug reactions (3.64%) were identified as serious. Six hundred seventy-one adverse drug reactions (61%) were preventable. Posttransplant duration was significantly correlated with the number of adverse drug reactions (R=0.19; P = .035). All renal allograft recipients experienced at least 1 immunosuppressant-related adverse reaction. Prolongation of immunosuppressive treatment resulted in an increase in adverse drug reactions.

To implement a computer-based adverse drug reaction monitoring system and compare its results with those of stimulated spontaneous reporting, and to assess the excess lengths of stay and costs of patients with verified adverse drug reactions. A prospective cohort study was used to assess the efficacy of computer-based monitoring, and case-matching was used to assess excess length of stay and costs. This was a study of all patients admitted to a medical ward of a university hospital in Germany between June and December 1997. 379 patients were included, most of whom had infectious, gastrointestinal or liver diseases, or sleep apnoea syndrome. Patients admitted because of adverse drug reactions were excluded. All automatically generated laboratory signals and reports were evaluated by a team consisting of a clinical pharmacologist, a clinician and a pharmacist for their likelihood of being an adverse drug reaction. They were classified by severity and causality. For verified adverse drug reactions, control patients with similar primary diagnosis, age, gender and time of admission but without adverse drug reactions were matched to the cases in order to assess the excess length of hospitalisation caused by an adverse drug reaction. Adverse drug reactions were detected in 12% of patients by the computer-based monitoring system and stimulated spontaneous reporting together (46 adverse reactions in 45 patients) during 1718 treatment days. Computer-based monitoring identified adverse drug reactions in 34 cases, and stimulated spontaneous reporting in 17 cases. Only 5 adverse drug reactions were detected by both methods. The relative sensitivity of computer-based monitoring was 74% (relative specificity 75%), and that of stimulated spontaneous reporting was 37% (relative specificity 98%). All 3 serious adverse drug reactions were detected by computer-based monitoring, but only 2 out of the 3 were detected by stimulated spontaneous reporting. The percentage of automatically generated laboratory signals associated with an adverse drug reaction (positive predictive value) was 13%. The mean excess length of stay was 3.5 days per adverse drug reaction. 48% of adverse reactions were predictable and detected solely by computer-based monitoring. Therefore, the potential for savings on this ward from the introduction of computer-based monitoring can be calculated as EUR56 200/year ($US59 600/year) [ 1999 values]. Computer monitoring is an effective method for improving the detection of adverse drug reactions in inpatients. The excess length of stay and costs caused by adverse drug reactions are substantial and might be considerably reduced by earlier detection.

The terms 'adverse drug effects' and 'adverse drug reactions' are commonly used interchangeably, but they have different implications. Adverse drug reactions arise when a compound (e.g. a drug or metabolite, a contaminant or adulterant) is distributed in the same place as a body tissue (e.g. a receptor, enzyme, or ion channel), and the encounter results in an adverse effect (a physiological or pathological change), which results in a clinically appreciable adverse reaction. Both the adverse effect and the adverse reaction have manifestations by which they can be recognized: adverse effects are usually detected by laboratory tests (e.g. biochemical, haematological, immunological, radiological, pathological) or by clinical investigations (e.g. endoscopy, cardiac catheterization), and adverse reactions by their clinical manifestations (symptoms and/or signs). This distinction suggests five scenarios: (i) adverse reactions can result directly from adverse effects; (ii) adverse effects may not lead to appreciable adverse reactions; (iii) adverse reactions can occur without preceding adverse effects; (iv) adverse effects and reactions may be dissociated; and (v) adverse effects and reactions can together constitute syndromes. Defining an adverse drug reaction as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product" suggests a definition of an adverse drug effect: "a potentially harmful effect resulting from an intervention related to the use of a medicinal product, which constitutes a hazard and may or may not be associated with a clinically appreciable adverse reaction and/or an abnormal laboratory test or clinical investigation, as a marker of an adverse reaction."

Drug-induced skin ulcers: A disproportionality analysis from the WHO pharmacovigilance database

Immune-Mediated and Adverse Drug Reactions During Treatment with the Fifth Generation Cephalosporin, Ceftaroline: Drug Allergy Matters

BackgroundRapid dissemination of information regarding adverse drug reactions is a key aspect for improving pharmacovigilance. There is a possibility that unknown adverse drug reactions will become apparent through post-marketing administration. Currently, although there have been studies evaluating the relationships between a drug and adverse drug reactions using the JADER database which collects reported spontaneous adverse drug reactions, an efficient approach to assess the association between adverse drug reactions of drugs with the same indications as well as the influence of demographics (e.g. gender) has not been proposed.Methods and FindingsWe utilized the REAC and DEMO tables from the May 2015 version of JADER for patients taking antidepressant drugs (SSRI, SNRI, and NaSSA). We evaluated the associations using association analyses with an apriori algorithm. Support, confidence, lift, and conviction were used as indicators for associations. The highest score in adverse drug reactions for SSRI was obtained for "aspartate aminotransferase increased", "alanine aminotransferase increased", with values of 0.0059, 0.93, 135.5, and 13.9 for support, confidence, lift and conviction, respectively. For SNRI, "international normalized ratio increased", "drug interaction" were observed with 0.0064, 1.00, 71.9, and NA. For NaSSA, "anxiety", "irritability" were observed with 0.0058, 0.80, 49.9, and 4.9. For female taking SSRI, the highest support scores were observed in "twenties", "suicide attempt", whereas "thirties", "neuroleptic malignant syndrome" were observed for male. Second, for SNRI, "eighties", "inappropriate antidiuretic hormone secretion" were observed for female, whereas "interstitial lung disease" and "hepatitis fulminant" were for male. Finally, for NaSSA, "suicidal ideation" was for female, and "rhabdomyolysis" was for male.ConclusionsDifferent combinations of adverse drug reactions were noted between the antidepressants. In addition, the reported adverse drug reactions differed by gender. This approach using a large database for examining the associations can improve safety monitoring during the post-marketing phase.