Assessment of Substrate Status of Drugs Metabolized by Polymorphic Cytochrome P450 (CYP) 2 Enzymes: An Analysis of a Large-Scale Dataset.

BACKGROUND: The analysis of substrates of polymorphic cytochrome P450 (CYP) enzymes is important information to enable drug-drug interactions (DDIs) analysis and the relevance of pharmacogenetics in this context in large datasets. Our aim was to compare different approaches to assess the substrate properties of drugs for certain polymorphic CYP2 enzymes. METHODS: A standardized manual method and an automatic method were developed and compared to assess the substrate properties for the metabolism of drugs by CYP2D6, 2C9, and 2C19. The automatic method used a matching approach to three freely available resources. We applied the manual and automatic methods to a large real-world dataset deriving from a prospective multicenter study collecting adverse drug reactions in emergency departments in Germany (ADRED). RESULTS: In total, 23,878 medication entries relating to 895 different drugs were analyzed in the real-world dataset. The manual method was able to assess 12.2% (n = 109) of drugs, and the automatic method between 12.1% (n = 109) and 88.9% (n = 796), depending on the resource used. The CYP substrate classifications demonstrated moderate to almost perfect agreements for CYP2D6 and CYP2C19 (Cohen's Kappa (κ) 0.48-0.90) and fair to moderate agreements for CYP2C9 (κ 0.20-0.48). CONCLUSION: A closer look at different classifications between methods revealed that both methods are prone to error in different ways. While the automated method excels in time efficiency, completeness, and actuality, the manual method might be better able to identify CYP2 substrates with clinical relevance.

Nutrimetric Validation of Solanidine as Dietary-Derived CYP2D6 Activity Marker In Vivo.

CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary-derived activity marker for CYP2D6. The intraday variability in plasma within individuals has not been studied yet in healthy subjects. As part of a CYP phenotyping cocktail study with 20 healthy participants, plasma concentrations of solanidine, 4-OH-solanidine and 3,4-secosolanidine-3,4-dioic acid (SSDA) were determined using a sensitive liquid chromatography-mass spectrometry method in urine and in plasma at timepoints 0, 2.5, 5, 8, and 24 hours after intake of test substances. The participants were phenotyped for CYP2D6 with oral metoprolol (12.5 mg) with 15 plasma sampling points over 24 hours (DRKS00028922). Metabolic ratios (MRs) of metabolite to parent plasma concentrations were formed from single timepoints and the area under the curve (AUC). All participants were genotyped for CYP2D6. The intra-individual variability of the CYP2D6 metabolite SSDA was highly stable with a median SD of 11.62% over 24 hours. MR SSDA/solanidine was more variable (median SD 31.90%) but correlated significantly at all measured timepoints with AUC MR α-OH-metoprolol/metoprolol. The AUC MR SSDA/solanidine showed a significant linear relationship with the genetically predicted CYP2D6 activity score. This study substantiates the MR SSDA/solanidine as CYP2D6 activity marker. The high correlation with metoprolol MR indicates a valid prediction of the CYP2D6 phenotype at any timepoint during the study day.

Use of overactive bladder anticholinergic medications associated with falls leading to emergency department visits: results from the ADRED study.

PURPOSE: Drug intake might be a modifiable factor for the individual fall-risk of older adults, and anticholinergic properties of drugs need to be considered. This study is aimed at analyzing the association of older adults' individual anticholinergic load with particular focus on use of overactive bladder anticholinergic medications with falls in multi-medicated patients. MATERIALS AND METHODS: Cases of the prospective, observational, multi-center study on adverse drug reactions leading to emergency departments (ADRED study) between 2015 and 2018 in Germany were analyzed comparing the exposure of overactive bladder anticholinergic medications on the chance to present with a fall with patients without exposure. Logistic regression analysis was used adjusting for pre-existing conditions, drug exposure, and the individual anticholinergic burden by drug use. To this end, a combination of seven expert-based anticholinergic rating scales was used. RESULTS: The anticholinergic burden was higher in patients with overactive bladder anticholinergic medications (median 2 [1; 3]) compared to not taking drugs of interest. Presenting with a fall was associated with overactive bladder anticholinergic medications (odds ratio (OR) 2.34 [95% confidence interval 1.14-4.82]). The use of fall-risk increasing drugs was likewise associated (OR 2.30 [1.32-4.00]). The anticholinergic burden itself seemed not to be associated with falls (OR 1.01 [0.90-1.12]). CONCLUSIONS: Although falls occur multifactorial in older adults and confounding by indication cannot be ruled out, the indication for a drug treatment should be decided with caution when other, non-pharmacological treatment options have been tried. GERMAN CLINICAL TRIAL REGISTER: DRKS-ID: DRKS00008979, registration date 01/11/2017.

A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study.

BACKGROUND: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. METHODS: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. FINDINGS: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001). INTERPRETATION: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. FUNDING: European Union Horizon 2020.

Inhalation therapies in COPD - adverse drug reactions impact on emergency department presentations.

PURPOSE: Inhaled drugs have been cornerstones in the treatment of chronic obstructive pulmonary disease (COPD) for decades and show a high prescription volume. Due to the local application, drug safety issues of these therapies are often underestimated by professionals and patients. Data about adverse drug reactions (ADRs) caused by inhaled therapy in patients with COPD and polypharmacy are rare. We aimed to analyze the use and relevance of inhaled therapies in those patients in relation to ADR complaints, which were severe enough to warrant presentation to the emergency department. METHODS: Emergency department cases due to suspected ADRs of the ADRED database (n = 2939, "Adverse Drug Reactions in Emergency Departments"; DRKS-ID: DRKS00008979, registration date 01/11/2017) were analyzed for inhaled drugs in patients with COPD. ADRs in cases with overdosed inhaled drugs were compared to non-overdosed cases. ADRs, potentially caused by inhaled drugs, were evaluated, clustered into complexes, and assessed for association with inhaled drug classes. RESULTS: Of the 269 included COPD cases, 67% (n = 180) received inhaled therapy. In 16% (n = 28), these therapies were overdosed. Overdosed cases presented the complexes of malaise and local symptoms more frequently. Related to the use of inhaled anticholinergics, local (dysphagia-like) and related to inhaled beta-2 agonists, local (dysphagia-like) and sympathomimetic-like ADRs presented more frequently. CONCLUSION: Overdosed inhaled therapies in patients with COPD lead to relevant ADRs and impact on emergency room presentations. These are rarely associated to inhaled therapy by healthcare professionals or patients. Due to the high volume of inhaled drug prescriptions, pharmacovigilance and patient education should be more focused in patients with COPD. German Clinical Trial Register: DRKS-ID: DRKS00008979.

Emergency Department Visits Due to Dyspnea: Association with Inhalation Therapy in COPD and Cases with Adverse Drug Reactions.

Purpose: Dyspnea is a leading symptom of COPD that causes presentations in emergency departments or negatively impacts on them. Guideline-based inhalation therapies are intended to reduce dyspnea in COPD patients. This study analyzed how common guideline recommended inhalation therapy regimens are occurring in clinical practice among COPD patients presenting to emergency departments due to adverse drug reactions in polytherapy using data of the German ADRED database. Patients and Methods: In total, 269 COPD cases were identified. In a further analysis, all cases were analyzed for documented GOLD stage and guideline-recommended inhalation therapy for COPD. Dyspnea and other symptoms identified during ED presentation were analyzed and compared between patients who did and did not receive the guideline's recommended inhalation therapy. Results: In this observation, 41% (n = 46) of all 112 cases with a documented COPD and GOLD stage received an underdosed therapy according to current guidelines. Dyspnea was the most common identified symptom (32%, n = 36) in this cohort and occurred more often in patients who received an underdosage of inhalation therapy (p < 0.01). Conclusion: Patients with COPD presenting to ED with ADRs show a high rate of non-guideline-recommended inhalation therapy and present more often with dyspnea compared to those COPD patients who received an adequate dosing of inhalation therapy.

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant - implications for precision dosing in a global perspective.

Ketamine and its enantiomer S-ketamine (esketamine) are known to produce rapid-onset antidepressant effects in major depression. Intranasal esketamine has recently come onto the market as an antidepressant. Besides experience from short-term use in anaesthesia and analgesia, the experience with ketamine as long-term medication is rather low. The use of ketamine and esketamine is limited due to potential neurotoxicity, psychotomimetic side effects, potential abuse and interindividual variability in treatment response including cessation of therapy. Therefore, taking a look at individual patient risks and potential underlying variability in pharmacokinetics may improve safety and dosing of these new antidepressant drugs in clinical practice. Differential drug metabolism due to polymorphic cytochrome P450 (CYP) enzymes and gene-drug interactions are known to influence the efficacy and safety of many drugs. Ketamine and esketamine are metabolized by polymorphic CYP enzymes including CYP2B6, CYP3A4, CYP2C9 and CYP2A6. In antidepressant drug therapy, usually multiple drugs are administered which are substrates of CYP enzymes, increasing the risk for drug-drug interactions. We reviewed the potential impact of polymorphic CYP variants and common drug-drug interactions in antidepressant drug therapy affecting ketamine pharmacokinetics, and the role for dose optimization. The use of ketamine or intranasal esketamine as antidepressants demands a better understanding of the factors that may impact its metabolism and efficacy in long-term use. In addition to other clinical and environmental confounders, prior information on the pharmacodynamic and pharmacokinetic determinants of response variability to ketamine and esketamine may inform on dose optimization and identification of individuals at risk of adverse drug reactions.

Individualized versus Standardized Risk Assessment in Patients at High Risk for Adverse Drug Reactions (The IDrug Randomized Controlled Trial)-Never Change a Running System?

The aim of this study was to compare effects of an individualized with a standardized risk assessment for adverse drug reactions to improve drug treatment with antithrombotic drugs in older adults. A randomized controlled trial was conducted in general practitioner (GP) offices. Patients aged 60 years and older, multi-morbid, taking antithrombotic drugs and at least one additional drug continuously were randomized to individualized and standardized risk assessment groups. Patients were followed up for nine months. A composite endpoint defined as at least one bleeding, thromboembolic event or death reported via a trigger list was used. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. In total, N = 340 patients were enrolled from 43 GP offices. Patients in the individualized risk assessment group met the composite endpoint more often than in the standardized group (OR 1.63 [95%CI 1.02-2.63]) with multiple adjustments. The OR was higher in patients on phenprocoumon treatment (OR 1.99 [95%CI 1.05-3.76]), and not significant on DOAC treatment (OR 1.52 [95%CI 0.63-3.69]). Pharmacogenenetic variants of CYP2C9, 2C19 and VKORC1 were not observed to be associated with the composite endpoint. The results of this study may indicate that the time point for implementing individualized risk assessments is of importance.

[Current Challenges in Pharmacotherapy]. / Präoperative Medikation: aktuelle Herausforderungen in der Pharmakotherapie.

Analysis of preoperative medication is used to assess the benefit and risk associated with continuing or discontinuing medication before and during surgery. Identifying adverse drug reactions and assessing its risks often leads to uncertainty. Typical challenges are medication underuse, but also overuse occurs and is often more difficult to recognize, especially in the context of drug interactions and individual patient characteristics.Typical consequences of multi-medication and medical overuse may include an increased potential for drug interactions, an increased risk of adverse drug reactions and medication errors, and in particular in older adults, geriatric syndromes may occur or worsen. Adverse drug reactions may occur as a result of the dose administered and as an effect of time of exposure. Older, multi-morbid, and multi-medicated patients are often affected by adverse drug reactions. For drugs primarily metabolized via the phase I enzymes CYP2D6, CYP2C9, or CYP2C19, pharmacogenetically rapid or slow metabolism may result in altered drug exposures. Clinically relevant pharmacokinetic drug interactions frequently occur with drugs primarily metabolized via the phase I enzyme CYP3A4.

CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations-Implication for Drug Safety, Dosing, and Individualized Therapy.

Adverse drug reactions (ADRs) are one of the major causes of morbidity and mortality worldwide. It is well-known that individual genetic make-up is one of the causative factors of ADRs. Approximately 14 million single nucleotide polymorphisms (SNPs) are distributed throughout the entire human genome and every patient has a distinct genetic make-up which influences their response to drug therapy. Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of antiretroviral, antimalarial, anticancer, and antidepressant drugs. These drug classes are commonly in use worldwide and face specific population variability in side effects and dosing. Parts of this variability may be caused by single nucleotide polymorphisms (SNPs) in the CYP2B6 gene that are associated with altered protein expression and catalytic function. Population variability in the CYP2B6 gene leads to changes in drug metabolism which may result in adverse drug reactions or therapeutic failure. So far more than 30 non-synonymous variants in CYP2B6 gene have been reported. The occurrence of these variants show intra and interpopulation variability, thus affecting drug efficacy at individual and population level. Differences in disease conditions and affordability of drug therapy further explain why some individuals or populations are more exposed to CYP2B6 pharmacogenomics associated ADRs than others. Variabilities in drug efficacy associated with the pharmacogenomics of CYP2B6 have been reported in various populations. The aim of this review is to highlight reports from various ethnicities that emphasize on the relationship between CYP2B6 pharmacogenomics variability and the occurrence of adverse drug reactions. In vitro and in vivo studies evaluating the catalytic activity of CYP2B6 variants using various substrates will also be discussed. While implementation of pharmacogenomic testing for personalized drug therapy has made big progress, less data on pharmacogenetics of drug safety has been gained in terms of CYP2B6 substrates. Therefore, reviewing the existing evidence on population variability in CYP2B6 and ADR risk profiles suggests that, in addition to other factors, the knowledge on pharmacogenomics of CYP2B6 in patient treatment may be useful for the development of personalized medicine with regards to genotype-based prescription.

Hypoglycemia in Older Adults: Time Trends and Treatment Differences in Patients Aged ≥75 Years With Type 2 Diabetes.

OBJECTIVES: Hypoglycemia is a potentially life-threatening drug event under antidiabetic treatment. The aim of the study was to examine time trends in severe hypoglycemia in older adults with type 2 diabetes mellitus (T2DM) and antidiabetic treatment. DESIGN: Multicenter prospective diabetes patient follow-up registry (DPV). SETTING AND PARTICIPANTS: Patients aged ≥75 years with T2DM and documented treatment between 2005 and 2019. METHODS: Outcomes of interest were rates of severe hypoglycemia, diabetes therapy, body mass index, HbA1c, and estimated glomerular filtration rate. Time trends of outcomes were analyzed in the whole cohort and compared between age groups (75-<80, 80-<85, ≥85 years). RESULTS: A total of 136,931 patients from 188 diabetes centers were included. The adjusted HbA1c decreased from 7.3% (95% confidence interval 7.3-7.4) in 2005 to 7.2% (7.2-7.2) in 2019 (P < .001), with no significant difference between age groups (P = .47). Rates of severe hypoglycemia decreased from 6.7 (6.0-7.4) to 4.1 of 100 person-years (3.7-4.5) (P < .001) in the entire population. Patients aged ≥85 years had constantly lower HbA1c levels compared with younger groups (P < .001). Although severe hypoglycemia decreased the most in the ≥85 age group (P < .001), severe hypoglycemia remained consistently higher in this group compared with the 75 to <80 years group (P < .001). CONCLUSIONS AND IMPLICATIONS: During the analyzed time, the risk for severe hypoglycemia decreased. Although drugs with intrinsic risk for hypoglycemia were used less frequently, antidiabetic treatment in older adults should be further improved to continue reducing severe hypoglycemia in this age group, potentially accepting less strict metabolic control and age-specific target ranges.

CYP2D6 in the Brain: Potential Impact on Adverse Drug Reactions in the Central Nervous System-Results From the ADRED Study.

Cytochrome P450 (CYP) 2D6 is a polymorphic enzyme expressed in the central nervous system (CNS), important in drug metabolism and with a potentially constitutive role in CNS function such as vigilance. This study aimed to analyze variability in CYP2D6 activity linked to vigilance-related adverse drug reactions (ADRs) in the CNS. A dataset of N = 2939 ADR cases of the prospective multicenter observational trial in emergency departments (EDs) (ADRED; trial registration: DRKS-ID: DRKS00008979) was analyzed. Dizziness as the most frequent reported CNS ADR symptom (12.7% of patients, n = 372) related to vigilance was chosen as the outcome. The association of dizziness with CYP2D6 activity markers was analyzed. The number of CYP2D6 substrates taken, a CYP2D6 saturation score (no, moderate, and strong saturation), a CYP2D6 saturation/inhibition score (no, weak, moderate, and strong), and composed CYP2D6 activity using a genotyped subsample (n = 740) calculating additive effects of genotype and CYP2D6 saturation by drug exposure were used as CYP2D6 activity markers. Effects were compared to other frequent nonvigilance-related CNS ADR symptoms (syncope and headache). Secondary analyses were conducted to control for other ADR symptoms frequently associated with dizziness (syncope, nausea, and falls). The majority of all patients (64.5%, n = 1895) took at least one drug metabolized by CYP2D6. Around a third took a CNS drug (32.5%, n = 955). The chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01-1.23]. Presenting with drug-related dizziness was more likely with CYP2D6 saturation and saturation/inhibition (both OR 1.27 [1.00-1.60]). The composed CYP2D6 activity was positively associated with dizziness (p = 0.028), while poorer activity affected patients more often with dizziness as an ADR. In contrast, nonvigilance-related ADR symptoms such as syncope and nausea were not consistently significantly associated with CYP2D6 activity markers. This study shows an association between the number of CYP2D6 substrates, the predicted CYP2D6 activity, and the occurrence of dizziness as a CNS ADR symptom. As dizziness is a vigilance-related CNS symptom, patients with low CYP2D6 activity might be more vulnerable to drug-related dizziness. This study underlines the need for understanding individual drug metabolism activity and individual risks for ADRs.

Fall-Associated Drugs in Community-Dwelling Older Adults: Results from the ActiFE Ulm Study.

OBJECTIVES: Many studies describing an association of drugs with falls focus mostly on drugs acting in the central nervous system. We aim to analyze the association of all drugs taken with falls in older adults. DESIGN: Prospective population-based study (ActiFE study). SETTING AND PARTICIPANTS: A total of 1377 community-dwelling older adults with complete recording of falls and baseline information on drug intake. METHODS: Negative binomial regression was used to analyze the association of 34 drug classes with a 12-month incidence rate ratio (IRR) of falls adjusting for age, sex, comorbidities, gait speed, balance, chair rise, kidney function, liver disease, and smoking. RESULTS: Participants took a median 3 drugs (interquartile range 1, 5), with 34.5% (n = 469) having ≥5 drugs. The median IRR for a fall per person-year was overall 0.72 [95% confidence interval (CI) 0.60-0.83] and 2.22 (95% CI 1.90-2.53) among those who experienced ≥1 fall. The following drug classes showed significant associations: antiparkinsonian medication [IRR 2.68 (95% CI 1.59-4.51)], thyroid therapy [IRR 1.40 (95% CI 1.08-1.81)], and systemic corticosteroids [IRR 0.33 (95% CI 0.13-0.81)]. Among fall-risk-increasing drugs only antiepileptics [IRR 2.16 (95% CI 1.10-4.24)] and urologicals [IRR 2.47 (95% CI 1.33-4.59)] were associated with falls in those participants without a prior fall history at baseline. CONCLUSION AND IMPLICATIONS: Additional drug classes, such as antiparkinsonian medication, thyroid therapy, and systemic corticosteroids, might be associated with falls in older adults, possibly representing pharmacological effects on the musculoskeletal and central nervous systems. Further evaluations in larger study populations are recommended.

Adverse Drug Reactions in the Emergency Department: Is There a Role for Pharmacogenomic Profiles at Risk?-Results from the ADRED Study.

Individual differences in required drug dosages exist based on the pharmacogenomic (PGx) profiles. This study aimed to assess associations between PGx profiles and adverse drug reactions (ADR) that lead to admissions to the emergency department (ED). ADR cases of the prospective multi-center observational trial in EDs (ADRED study) were analyzed (n = 776) together with the relevant PGx phenotypes of the enzymes CYP2D6, CYP2C19, CYP2C9, and VKORC1. Overall, the allele frequency distribution in this cohort did not differ from the population frequencies. We compared the frequencies of phenotypes in the subgroups with the drugs suspected of certain ADR, in the remaining cases. The frequency distribution of CYP2C19 differed for the ADR bleeding cases suspected of clopidogrel (p = 0.020). In a logistic regression analysis, higher CYP2C19 activity (OR (95% CI): 4.97 (1.73-14.27)), together with age (1.05 (1.02-1.08)), showed an impact on the clopidogrel-suspecting ADRs, when adjusting for the clinical parameters. There was a trend for an association of phenprocoumon-risk profiles (low VKORC1 or CYP2C9 activity) with phenprocoumon-suspecting ADRs (p = 0.052). The PGx impact on serious ADRs might be highest in drugs that cannot be easily monitored or those that do not provoke mild ADR symptoms very quickly. Therefore, patients that require the intake of those drugs with PGx variability such as clopidogrel, might benefit from PGx testing.

The phenotype of adverse drug effects: Do emergency visits due to adverse drug reactions look different in older people? Results from the ADRED study.

AIMS: Older patients in particular suffer from adverse drug reactions (ADR) when presenting in the emergency department. We aimed to characterise the phenotype of those ADRs, to be able to recognise an ADR in older patients. METHODS: Cases of ADRs in emergency departments collected within the multicentre prospective observational study (ADRED) were analysed (n = 2215). We analysed ADR-associated diagnoses, symptoms and their risk profiles. We present frequencies and odds ratios (OR) with 95% confidence intervals for adults (18-64 years) compared to older adults (≥65 years; young-old 65-79, old-old ≥80 years) and regression coefficients (B) for each year of age. RESULTS: Most prominent differences were seen for drug-associated confusion, dehydration, and bradycardia (OR 6.70 [1.59-28.27], B .054; OR 6.02 [2.41-15.03], B .081, and 4.82 [2.21-10.54], B .040), more likely seen in older adults. Bleedings were reported in all age groups, but gastrointestinal bleedings occurred with more than doubled chance in older adults (OR 2.46 [1.77-3.41], B .030), likewise did other bleedings such as haemorrhage from respiratory passages (OR 2.89 [1.37-6.11], B.036). Falls were more likely in older adults (OR 2.84 [1.77-4.53], B .030), while dizziness was frequent in both age groups. CONCLUSION: Our data point to differences in symptoms of ADRs between adults and older individuals, with dangerous drug-associated phenomena in the older adult such as bleedings or falls. Physicians should consider drug-associated origins of symptoms in older adults with an increased risk for serious health problems.

Adverse drug reactions in older adults: a retrospective comparative analysis of spontaneous reports to the German Federal Institute for Drugs and Medical Devices.

BACKGROUND: Older adults are more prone to develop adverse drug reactions (ADRs) since they exhibit numerous risk factors. The first aim was to analyse the number of spontaneous ADR reports regarding older adults (> 65) in the ADR database of the German Federal Institute for Drugs and Medical Devices (BfArM) and to set them in relation to i) the number of ADR reports concerning younger adults (19-65), and ii) the number of inhabitants and assumed drug-exposed inhabitants. The second aim was to analyse, if reported characteristics occurred more often in older vs. younger adults. METHODS: All spontaneous ADR reports involving older or younger adults within the period 01/01/2000-10/31/2017 were identified in the ADR database. Ratios concerning the number of ADR reports/number of inhabitants and ADR reports/drug-exposed inhabitants were calculated. The reports for older (n = 69,914) and younger adults (n = 111,463) were compared using descriptive and inferential statistics. RESULTS: The absolute number of ADR reports involving older adults increased from 1615 (2000) up to 5367 ADR reports (2016). The age groups 76-84 and 70-79 had the highest number of ADR reports with 25 ADR reports per 100,000 inhabitants and 27 ADR reports per 100,000 assumed drug-exposed inhabitants. For both ratios, the number of reports was higher for males (26 and 28 ADR reports) than for females (24 and 26 ADR reports). Fatal outcome was reported almost three times more often in older vs. younger adults. Six out of ten drug substances most frequently suspected were antithrombotics (vs. 1/10 in younger adults). For some drug substances (e.g. rivaroxaban) the ADRs reported most frequently differed between older (epistaxis) and younger adults (menorrhagia). CONCLUSIONS: There is a need to further investigate ADRs in older adults since they occurred more frequently in older vs. younger adults and will likely increase in future. Physicians should be aware of different ADRs being attributed to the same drug substances which may be more prominent in older adults. Regular monitoring of older adults taking antithrombotics is recommended.

Prevalence of Psychotropic Drugs in Cases of Severe Adverse Drug Reactions Leading to Unplanned Emergency Visits in General Hospitals.

INTRODUCTION: The prevalence of psychotropic drug use in our society is increasing especially in older adults, thereby provoking severe adverse drug reactions (ADR). To identify specific patient risk profiles associated with psychotropic drug use in the situation of polymedication. METHODS: Cases of ADRs in general emergency departments (ED) collected within the multi-center prospective observational study (ADRED) were analyzed (n=2215). We compared cases with use of psychotropic drugs and without concerning their clinical presentation at the ED. RESULTS: A third of patients (n=731, 33%) presenting to the ED with an ADR took at least 1 psychotropic drug. Patients with psychotropic drug use tended to be older, more often female, and took a higher number of drugs (all p<0.001). The frequency of falls was almost 3 times higher than compared to the non-psychotropic drug group (10.5 vs. 3.9%, p<0.001), and similar syncope was also more often seen in the psychotropic drug users (8.8 vs. 5.5%, p=0.004). The use of psychotropic drugs increased the risk for falls by a factor of 2.82 (OR, 95% CI (1.90-4.18)), when adjusting for gender, age, numbers of pre-existing diseases, and drugs, respectively. DISCUSSION: The association of psychotropic drug use with fall and syncope in combination with polymedication and older age leads to the suspicion that psychotropic drugs might be potentially harmful in specific risk populations such as older adults. It may lead us to thoroughly weigh the benefit against risk in a patient-oriented way, leading to an integrative personalized therapy approach.

Personalising drug safety-results from the multi-centre prospective observational study on Adverse Drug Reactions in Emergency Departments (ADRED).

PURPOSE: Adverse drug reactions (ADR) account for 5 to 7% of emergency department (ED) consultations. We aimed to assess medication risk profiles for ADRs leading to ED visits. METHODS: We analysed medication intake and patient demographics in a prospective multi-centre observational study collecting ADR cases in four large EDs in Germany. Odds ratios (OR) were calculated to relate drug classes taken to those suspicious for an ADR after a causality assessment. RESULTS: A total of 2215 cases of ED visits due to ADRs were collected. The median age of the cohort was 73 years; in median, six co-morbidities and an intake of seven drugs were documented. Antineoplastic/immunomodulating agents had the highest OR for being suspected for an ADR (OR 20.45, 95% CI 14.54-28.77), followed by antithrombotics (OR 2.94, 95% CI 2.49-3.47), antibiotics (OR 2.65, 95% CI 1.78-3.95), systemic glucocorticoids (OR 2.43, 95% CI 1.54-3.82) and drugs affecting the central nervous system (CNS), such as antipsychotics (OR 2.36, 95% CI 1.46-3.81), antidepressants (OR 2.10, 95% CI 1.57-2.83), antiparkinsonian medication (OR 2.11, 95% CI 1.15-3.84), opioids (OR 1.79, 95% CI 1.26-2.54) and non-opioid analgesics (OR 1.32, 95% CI 1.01-1.72). CONCLUSIONS: Patients experiencing ADRs leading to ED visits are commonly old, multi-morbid and multi-medicated. CNS drugs may be more relevant than prior expected. With calculating ORs, we could replicate involvement of antineoplastic agents, antithrombotics, antibiotics, systemic glucocorticoids and non-opioid analgesics as frequently suspected for ADRs in EDs. TRIAL REGISTRATION: DRKS-ID: DRKS00008979.

Adverse Drug Reactions (ADR) and Emergencies.

BACKGROUND: Adverse drug reactions (ADR) are a common reason for emergency room visits and for hospitalization. An ADR is said to have occurred when the patient's symptoms and signs are considered to be possibly, probably, or definitely related to the intake of a drug. METHODS: In four large hospital emergency departments, one in each of four German cities ( Ulm, Fürth, Bonn, and Stuttgart), the percentage of suspected ADR cases among all patients presenting to the emergency room was determined during a 30-day period of observation. ADRs were ascertained by screening the digital records of all patients seen in the emergency room; causality was assessed as specified by the WHO-UMC (Uppsala Monitoring Center). RESULTS: ADR were sought in a total of 10 174 emergency department visits. 665 cases of suspected ADR were found, yielding a prevalence of 6.5%. The prevalence of ADR among patients with documented drug intake was 11.6%. Among the patients with documented suspected ADRs, 89% were hospitalized (in contrast to the 43.7% hospitalization rate in the entire group of 10 174 emergency department visits). A possible causal relationship between the patient's symptoms and signs and the intake of a drug was found in 74-84% of cases. Patients with ADR were found to be taking a median of 7 different drugs simultaneously. CONCLUSION: Adverse drug reactions are a relevant cause of emergency department visits, accounting for 6.5% of the total visits in this study, and often lead to hospital admission. The ADRED (Adverse Drug Reactions in Emergency Departments) study, which is now being conducted, is intended to shed further light on their causes, patient risk factors, and potential avoidability.