Risk Of Serious Adverse Drug Reactions Research Articles

Kidney Function Decline and Serious Adverse Drug Reactions in Patients With CKD

Adverse drug reactions (ADRs) are common in patients with chronic kidney disease (CKD). The impact of kidney function decline on serious ADR risk has been poorly investigated. We comprehensively describe ADRs and assess the relationship between estimated glomerular filtration rate (eGFR) and serious ADR risk. Prospective cohort study. 3,033 participants in French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study, a nationwide sample of nephrology outpatients with moderate to advanced CKD. Demographic and biological data (including eGFR), medication prescriptions. ADRs (preventable or not) were prospectively identified from hospital discharge reports, medical records, and patient interviews. Expert pharmacologists used validated tools to adjudicate ADRs. Restricted cubic splines in fully adjusted cause-specific Cox proportional hazard models were used to evaluate the relationship between eGFR and the risk of serious ADRs (overall and by subtype). During a median follow-up period of 4.7 years, 360 patients experienced 488 serious ADRs. Kidney and urinary disorders (n=170) and hemorrhage (n=170) accounted for 70% of serious ADRs. The most common medications classes were antithrombotics and renin-angiotensin system inhibitors. The majority of those serious ADRs were associated with hospitalization (n=467), with 32 directly or indirectly associated with death and 22 associated with a life-threatening event. More than 27% of the 488 serious ADRs were preventable or potentially preventable. The eGFR is a major risk factor for serious ADRs. The risk of acute kidney injury was 2.2% higher and risk of bleeding ADRs was 8% higher for each 1mL/min/1.73m2 lower baseline eGFR. The results cannot be extrapolated to patients who are not being treated by a nephrologist. ADRs constitute a major cause of hospitalization in CKD patients for whom lower eGFR level is a major risk factor. Patients with chronic kidney disease (CKD) have complex clinical presentations, take multiple medications, and often receive inappropriate prescriptions. Using data from a large, prospective CKD cohort, we found a high incidence of serious adverse drug reactions (ADRs). The 2 most common serious ADRs were drug-induced acute kidney injury and bleeding. A large proportion of serious ADRs required hospital admission, and 11% led to death or were life threatening. Lower kidney function was a major risk factor for serious ADRs. Many of these serious ADRs were determined to be partly preventable through greater adherence to prescription guidelines. This report enhances our understanding of the potential toxicity of drugs taken by patients with moderate to advanced CKD. It emphasizes the importance of monitoring kidney function when prescribing drugs, particularly for high-risk medications such as antithrombotic agents.

Serious Adverse Drug Reactions in Children and Adolescents Treated On- and Off-Label with Antidepressants and Antipsychotics in Clinical Practice.

Introduction Despite the growing evidence base for psychotropic drug treatment in pediatric patients, knowledge about the benefit-risk ratio in clinical practice remains limited. The ‘Therapeutic Drug Monitoring (TDM)-VIGIL’ study aimed to evaluate serious adverse drug reactions (ADRs) in children and adolescents treated with antidepressants and/or antipsychotics in approved (‘on-label’), and off-label use in clinical practice. Methods Psychiatric pediatric patients aged 6-18 years treated with antidepressants and/or antipsychotics either on-label or off-label were prospectively followed between October 2014 and December 2018 within a multicenter trial. Follow-up included standardized assessments of response, serious ADRs and therapeutic drug monitoring. Results 710 youth (age=14.6±2.2 years, female=66.6%) were observed for 5.5 months on average; 76.3% received antidepressants, 47.5% antipsychotics, and 25.2% both. Altogether, 55.2% of the treatment episodes with antidepressants and 80.7% with antipsychotics were off-label. Serious ADRs occurred in 8.3% (95%CI=6.4–10.6%) of patients, mainly being psychiatric adverse reactions (77.4%), predominantly suicidal ideation and behavior. The risk of serious ADRs was not significantly different between patients using psychotropics off-label and on-label (antidepressants: 8.1% vs. 11.3%, p=0.16; antipsychotics: 8.7% vs 7.5%, p=0.67). Serious ADRs occurred in 16.6% of patients who were suicidal at enrollment versus 5.6% of patients who were not suicidal (relative risk 3.0, 95%CI=1.9-4.9). Conclusion Off-label use of antidepressants and antipsychotics in youth was not a risk factor for the occurrence of serious ADRs in a closely monitored clinical setting. Results from large naturalistic trials like ours can contribute to bridging the gap between knowledge from randomized controlled trials and real-world clinical settings.

Using Pharmacogenetics of Direct Oral Anticoagulants to Predict Changes in Their Pharmacokinetics and the Risk of Adverse Drug Reactions.

Dabigatran, rivaroxaban, apixaban, and edoxaban are direct oral anticoagulants (DOACs) that are increasingly used worldwide. Taking into account their widespread use for the prevention of thromboembolism in cardiology, neurology, orthopedics, and coronavirus disease 2019 (COVID 19) as well as their different pharmacokinetics and pharmacogenetics dependence, it is critical to explore new opportunities for DOACs administration and predict their dosage when used as monotherapy or in combination with other drugs. In this review, we describe the details of the relative pharmacogenetics on the pharmacokinetics of DOACs as well as new data concerning the clinical characteristics that predetermine the needed dosage and the risk of adverse drug reactions (ADRs). The usefulness of genetic information before and shortly after the initiation of DOACs is also discussed. The reasons for particular attention to these issues are not only new genetic knowledge and genotyping possibilities, but also the risk of serious ADRs (primarily, gastrointestinal bleeding). Taking into account the effect of the carriership of single nucleotide variants (SNVs) of genes encoding biotransformation enzymes and DOACs metabolism, the use of these measures is important to predict changes in pharmacokinetics and the risk of ADRs in patients with a high risk of thromboembolism who receive anticoagulant therapy.

Assessing risk of adverse drug reactions in the elderly: a feasibility study.

Background Adverse drug reactions are common in Australian general practice and can be a cause of, or contribute to, preventable hospital admissions. Developing practical tools to assist in identifying patients who are at high risk of seriousadverse drug reactions is an important step in preventing these hospitalisations. Objective The aims of the study were to apply the Prediction of Hospitalisation due to Adverse Drug Reactions in Elderly Community-Dwelling Patients (PADR-EC) Score to assess the risk of medication-related hospitalisation among patients aged ≥ 65years attending a rural general practice, and to investigate general practitioners' acceptance of the PADR-EC Score. Setting The project was based in a multicentre rural general practice in southern Tasmania, Australia. Method We conducted a cross-sectional study wherein the PADR-EC score was administered to patients aged ≥ 65years attending a general practice. A focus group of general practice doctors was conducted and thematic analysis of the transcript used to explore their views regarding the utility of the PADR-EC score. Main Outcome Measures Successful application of the PADR-EC Score and an evaluation of general practitioners'acceptance of the PADR-EC Score are the two outcome measures of the project. Results The PADR-EC score was applied by the practice pharmacist and reported to GPs for 428 patients aged ≥ 65years, with 24.8% classified as high-risk. The focus group found the PADR-EC score helped raise awareness of the risk of adverse drug reactions in the general practice setting. Doctors demonstrated good understanding of the PADR-EC Score and there were no negative reactions to the delivery model used. No changes to prescribing were implemented directly as a result of the PADR-EC Score, but more caution was used when doctors provided their usual clinical care. Conclusion Doctors used the PADR-EC score to complement their decision making. The PADR-EC Score was used as a reminder to review existing medication lists, follow-up on pathology results that may impact drug treatment and assess patients for prevalent ADRs. Further research is needed to validate the PADR-EC score in this setting.

Characterization of serious adverse drug reactions as cause of emergency department visit in children: a 5-years active pharmacovigilance study

BackgroundTo describe frequency, preventability and seriousness of adverse drug reactions (ADRs) in children as cause of emergency department (ED) admission and to evaluate the association between specific factors and the reporting of ADRs.MethodsA retrospective analysis based on reports of suspected ADRs collected between January 1st, 2012 and December 31st, 2016 in the ED of Meyer Children’s Hospital (Italy). Demographics, clinical status, suspected drugs, ADR description, and its degree of seriousness were collected. Logistic regression was used to estimate the reporting odds ratios (RORs) with 95% confidence intervals (CIs) of potential predictors of ADR seriousness.ResultsWithin 5 years, we observed 834 ADRs (1100 drug-ADR pairs), of whom 239 were serious; of them, 224 led to hospitalization. Patients were mostly treated with one drug. Among patients treated with more than one drug, 78 ADRs presented a potential interaction. The most frequently reported ADRs involved gastrointestinal system. The most frequently reported medication class was antinfectives. Risk of serious ADR was significantly lower in children and infants compared to adolescents (ROR 0.41 [95% CI: 0.27–0.61] and 0.47 [0.32–0.71], respectively), and it was significantly increased in subjects exposed to more than one drug (ROR 1.87 [1.33–2.62] and 3.01 [2.07–4.37] for subjects exposed to 2 and 3 or more drugs, respectively). Gender, interactions and off-label drug use did not influence the risk of serious ADRs.ConclusionActive surveillance in pharmacovigilance might represent the best strategy to estimate and characterize the clinical burden of ADRs in children.

Adverse drug reactions associated with off-label use of ketorolac, with particular focus on elderly patients. An analysis of the Italian pharmacovigilance database and a population based study

ABSTRACTObjective: This study aims to evaluate the frequency of off-label use of ketorolac in Italy and the related suspected adverse drug reactions (ADRs) reported.Methods: All the suspected cases associated with ketorolac recorded in the Italian Pharmacovigilance database were retrieved. Case evaluations were carried out in order to identify the off-label use of ketorolac. Moreover, an analysis of the inappropriate use of ketorolac was conducted using the ‘Arianna’ database of Caserta local health unit.Results: Up to December 2014, 822 reports of suspected ADRs related to ketorolac were retrieved in the database. The use of ketorolac was classified as off-label for 553 reports and on-label for 269. Among the off-label cases, 58.6% were serious compared to 39.0% of on-label cases. Gastrointestinal events were more frequently reported with off-label use. The analysis of Arianna database showed that 37,729 out of 61,910 patients, were treated off-label.Conclusions: The off-label use of ketorolac is widespread in Italy. This use increases the risk of serious ADR, especially in in case of prolonged duration of treatment and in elderly patients. The Italian Medicine Agency has decided to accurately monitor the appropriate use of the drug in Italy and, if necessary, take measures in order to minimize the risks.

The pharmacotherapy of cirrhosis: concerns and proposed investigations and solutions.

The presence of cirrhosis has a multifaceted impact on hepatic drug metabolism. An area of concern and uncertainty in the care of patients with cirrhosis is the safe use of both prescription and over-the-counter medications. Retrospective studies indicate a high incidence of adverse drug reactions (ADRs) among patients with cirrhosis related to use of certain medication classes including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and non-steroidal anti-inflammatory drugs. Conversely, use of appropriate medications, such as statins, may be decreased in this population due to fear of precipitating hepatotoxicity. Pharmacotherapy in cirrhosis is an area of uncertainty and heterogeneity in clinical practice. Prescribing and dosing guidelines are needed to decrease the risk of serious ADRs in this high-risk patient population.

Serious adverse drug reactions to zolpidem: does impaired metabolic clearance and concurrent SSRI/SNRI use increase risk?

AbstractZolpidem is one of the most commonly used drugs for insomnia but it has been associated with adverse neuropsychiatric effects and complex sleep‐related behaviours. In this report, the pharmacokinetics, pharmacodynamics and putative serious adverse drug reactions (ADRs) to zolpidem are briefly described. Nine ‘hypothesis generating’ cases from a psychiatry practice are presented to suggest that in cytochrome P450 poor metabolisers, inhibitory metabolic drug–drug interactions and pharmacodynamic synergies with selective serotonin reuptake inhibitor/serotonin‐noradrenaline reuptake inhibitor antidepressants may increase the risk of serious ADRs to zolpidem.

Antiarrhythmic Drugs Use in Elderly Patients. Vaughan Williams Class III and IV Drugs

The effectiveness of antiarrhythmic drugs in the elderly is similar to that in younger patients. However data for «the very elderly» are lacking. Elderly patients are more vulnerable to adverse drug reactions (ADRs) because of age-related changes of pharmacokinetics, co-morbidity and drug interactions. Аmioadarone is not considered as the drug of choice in elderly patients because of the high risk of serious ADRs. Other class III drugs should be prescribed to the elderly with great caution under close monitoring of the treatment. Diltiazem and verapamil should not be used in elderly patients with NYHA class III-IV heart failure and should not be combined with β-blockers.

13-year overview of serious adverse drug reactions following subcutaneous specific immunotherapy with a chemically modified allergen preparation.

Background:The Paul-Ehrlich-Institut (PEI) published an analysis of reports of adverse drug reactions (ADRs) in 2001 with test and therapy allergens from the period from 1991 to 2000. Possible risk factors were evaluated for the ADR reports classified as “serious”. During the analyzed period, modified semi-depot preparations (allergoids) induced between 0.01 % and 0.0005 % serious systemic reactions, i. e. one serious ADR occurred in 10,000 to 200,000 injections. No information was provided regarding the respective incidences in relation to the individual companies or preparations.Materials and methods:Within the scope of a 13-year analysis (2001–2013), the serious ADRs were analysed at HAL for the allergoid preparations PURETHAL® Pollen and Mites. As in the analysis of PEI, the frequency of serious ADRs was based on the estimated number of administered injections.Results:A total of 46 cases with serious ADRs were received. In 26 % of the cases, a serious ADR occurred during initial treatment after the first injection. In 82.6 % of the cases, the serious ADR occurred within the 30-minute observation period in the practice. Adrenaline was administered as emergency treatment in seven cases. Hospitalisations were initiated by the treating physician or by patients themselves in 45 cases. The duration of the hospital stay varied from a few hours up to three days for further monitoring. Serious ADRs occurred in 11 cases with mites and in 35 cases with pollen. If it is assumed that there are six injections in each vial, this yields an incidence of 0.00061 % (1 : 164,000). The frequency with mites (0.00093 %) was slightly higher than with pollen (0.00055 %).Conclusions:The allergoid preparations (pollen and mite allergens) showed a very low risk of serious ADRs, which was close to the lower level of incidence of 0.0005 % for allergoid preparations published by the PEI.

Adverse drug reactions in elderly subjects hospitalized in a specialized dementia management unit.

Drug prescriptions represent an actionable item in the prevention of adverse drug reactions (ADRs). The aims of this study were to identify risk factors for the occurrence of ADRs, and to describe symptoms and drug interactions. This was a longitudinal study over a period of 19 months in an acute geriatric ward specializing in the management of dementia. Independent risk factors for ADRs were identified by logistic regression. Drug interactions were also recorded. In total, 293 patients were included (age 82 ± 8 years). The prevalence of ADRs was 24 %. Patients were taking 8 ± 3 drugs per day; 72 (24.6 %) were taking more than three psychotropics. The main therapeutic classes prescribed were anxiolytics and hypnotics (57.7 %), antidementia drugs (54.6 %), antidepressants (54.3 %), antithrombotics (54.0 %), angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin II receptor blockers [ARBs] (37.5 %). The risk of ADRs was significantly higher in patients taking neuroleptics (odds ratio [OR] 2.04; 95 % confidence interval [CI] 1.06-3.92), ACEIs/ARBs (OR 2.07; 95 % CI 1.13-3.77) and antidementia drugs (OR 1.84; 95 % CI 1.01-3.36). The risk of serious ADRs was significantly higher in patients taking ACEIs/ARBs (OR 2.95; 95 % CI 1.40-6.21), type I, III or IV antiarrhythmics (OR 2.71; 95 % CI 1.07-6.88) or neuroleptics (OR 2.42; 95 % CI 1.09-5.40). Drug interactions were involved in 26.3 % (n = 21) of ADRs; the combination of an ADR plus a drug interaction was associated with increased severity (p = 0.02). Caution is needed when prescribing ACEIs/ARBs, neuroleptics, antidementia drugs, or certain types of antiarrhythmics in patients suffering from dementia. Psychotropics should be avoided because of the associated risk of ADRs and drug interactions.

Multiple drug exposure as a risk factor for the seriousness of adverse drug reactions

The aim of the present study was to validate the hypothesis that multiple drug exposure is an independent risk factor for serious adverse drug reactions (ADRs). Adverse drug reactions (ADRs) are an important cause of iatrogenic disease, the majority being preventable. Multiple drug exposure, ageing and female gender have been identified as important risk factors for an increased incidence of ADRs. ADR reports received by the central Portugal Regional Pharmacovigilance Unit, between January 2001 and December 2009, were studied. Nearly half (47.4%) of ADRs reports were considered serious, from which 66.7% reported multiple drug exposure (mean 3.07 ± 2.2; maximum 13). After adjusting for gender, simultaneous exposure to three or more drugs was significantly associated with an increased risk of serious ADRs [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.02-1.51]. The present results support that multiple drug exposure is an independent risk factor for serious ADRs. Such findings are of importance in both medicines benefit/risk ratio evaluations and patient safety monitoring. A new level of nursing involvement is needed in both the detection of ADRs and prevention of serious outcomes, particularly in high-risk patients.

Are novel drugs more risky for patients than less novel drugs?

The Food and Drug Administration has accelerated the approval of therapeutically novel drugs so that patients have faster access to innovative drug therapies. Little research, however, has examined the variation in risks among therapeutically novel and less novel drugs. Do drugs that represent greater novelty also entail greater risks for patients? This paper uses post-marketing drug safety surveillance data from the FDA to examine the adverse drug reactions (ADRs) associated with novel and less novel drugs. Negative binomial regressions are used to examine the impact of a drug's FDA novelty rating on its ADR count controlling for differences in drug utilization, the conditions being treated, disease characteristics, patient characteristics, drug review times, and year-specific effects. Results show that drugs deemed novel by the FDA are associated with a greater number of serious drug reactions, including those that result in hospitalization and death, than less novel drugs. These results suggest that novel drugs pose greater risk of serious ADRs for patients relative to less novel drugs.

The ever-emerging anti-inflammatories. Have there been any real advances?

Gastrointestinal (GI) Adverse Drug Reactions (ADRs) from the NSAIDs are a major cause of morbidity and mortality in arthritic patients taking these drugs. The recent much heralded development of COX-2 selective drugs (celecoxib, rofecoxib), the objective of which has been to spare inhibition of the production of COX-1 derived mucosal protective prostaglandins, may have represented an advance in reducing the risk of serious ADRs—ulcers and bleeding—but does not appear to have reduced the incidence of symptomatic side-effects (nausea, vomiting, epigastric pain/heartburn, abdominal discomfort) which are a major reason for withdrawal from NSAID therapy, especially in the long term. The rationale of COX-2 selectivity from these newer drugs is controversial since there may be pharmacokinetic differences from established carboxylate-NSAIDs that accounts for their apparent lower ulcerogenicity. Moreover, concerns have been recently expressed that as COX-2 is important in ulcer healing, control of prostacyclin production and renal function that they may have adverse reactions from these effects. Indeed, recent reports of enhanced risk of congestive heart failure with rofecoxib are of importance and may relate to impaired prostacyclin production. Moreover, there are other therapeutic strategies that have yielded equally low ulcerogenic NSAIDs (e.g. the prodrug, nabumetone; the established COX-2 inhibitory drug, nimesulide) and even the well-established NSAIDs ibuprofen and diclofenac have relatively low upper GI ulcerogenicity and have been used as benchmark standards in comparative trials of the newer “Oxib” drugs (celecoxib, rofecoxib). Much research interest has centred on the nitric oxide—donating NSAIDs (NO-NSAIDs). The rationale for donating NSAIDs being to counteract the vasoconstriction effects of NSAIDs but this has yet to be fully evaluated. It is not certain that this “antidote” approach will be acceptable as there may also be systemic effects of the nitrobutoxyl—or other NO-donors that may have toxicological consequences. Another strategy is the development of mixed COX-5 lipoxygenase (LOX) inhibitors—the progenitors of which were benoxaprofen and BW-755C. The rationale of reducing the potential for lipoxygenase mediated actions in the stomach (e.g. vasoconstriction, leucocyte accumulation). Clearly, the need to develop newer NSAIDs with lower risks of ulcers and bleeding as well as symptomatic ADRs is still representing a major challenge.