Associated Adverse Drug Reactions Research Articles

N-(2,3-dihydroxypropyl) carbamoyl side chain: a potentially significant factor for recurrent iodinated contrast medium-related adverse drug reactions.

To determine whether switching to contrast media based on the sharing of N-(2,3-dihydroxypropyl) carbamoyl side chain reduces the recurrence of iodinated contrast media (ICM)-associated adverse drug reactions (ADRs). This single-center retrospective study included 2133 consecutive patients (mean age ± SD, 56.1 ± 11.4 years; male, 1052 [49.3%]) who had a history of ICM-associated ADRs and underwent contrast-enhanced CT examinations. The per-patient and per-exam-based recurrence ADR rates were compared between cases of switching and non-switching the ICM from ICMs that caused the previous ADRs, and between cases that used ICMs with common and different carbamoyl side chains from ICMs that caused the previous ADRs. Downgrade rates (no recurrence or the occurrence of ADR less severe than index ADRs) were also compared. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis were additionally performed. In per-patient analysis, switching of ICM showed a lower recurrence rate (switching, 10.4% [100/965] vs. non-switching, 28.4% [332/1168]), with the adjusted odds ratio (OR) of 0.27 (95% CI: 0.21, 0.34; p < 0.001). The result was consistent in PSM (OR, 0.29 [95% CI: 0.22, 0.39]; p < 0.001), IPTW (OR, 0.28 [95% CI: 0.22, 0.36]; p < 0.001), and in per-exam analysis (5.5% vs. 13.8%; OR, 0.32 [95% CI: 0.27, 0.37]; p < 0.001). There was lower per-exam recurrence (5.0% [195/3938] vs. 7.8% [79/1017]; OR, 0.63 [95% CI: 0.47, 0.83]; p = 0.001) and higher downgrade rates (95.6% [3764/3938] vs. 93.3% [949/1017]; OR, 1.51 [95% CI: 1.12, 2.03]; p = 0.006) when using different side chain groups. Switching to an ICM with a different carbamoyl side chain reduced the recurrent ADRs and their severity during subsequent examinations. Switching to an iodinated contrast media with a different carbamoyl side chain reduced the recurrent adverse drug reactions and their severity during subsequent examinations.

Clinical Pertinence and Determinants of Potential Drug–Drug Interactions in Chronic Kidney Disease Patients: A Cross-sectional Study

Background: Chronic kidney disease (CKD) is one of the major health issues effecting around 15% of world population, and its further complications has raised the need of polypharmacy for management. But this polypharmacy also upsurges the risk of potential drug-drug interactions (pDDIs) in CKD patients, which may further be responsible for increased morbidity and mortality. Objective: The main objective is therefore to evaluate the distribution, severity, causes, associated drug interactions, and clinical relevance of determination of pDDIs in CKD patients. Methods: Medical files of CKD patients examined at nephrology department, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Mullana, between December 2022 and May 2023 were cross-sectionally assessed for this study. Medscape drug interaction checker was used to study patient profiles for pDDIs, and suggestive measures to minimize those pDDIs were studied using DDInter to ensure better clinical decision-making and patient safety. IBM SPSS (version 24) was utilized for statistical analysis. Results: The data reveal that 74.5% of the 200 medical files being evaluated had 839 pDDIs in total, out of which nearly 78.3% of patients had moderate, 15.6% had minor, and 6.07% had serious interactions. The potential adverse outcomes of pDDIs included an irregular heartbeat, hypokalemia, central nervous system (CNS) adverse effects, hypoglycemia, and a decline in therapeutic efficacy. The prevalence of pDDIs was discovered to be substantially correlated with age ≥60 years, (odds ratio [OR] = 0.65; 95% CI = 0.4-0.9; P = 0.040), length of stay ≥10 days (OR = 4.0; 95% CI = 1.29-6.1; P = 0.016), and number of prescribed drugs ≥10 (OR = 5.5; 95% CI = 2.45-10.69; P = 0.004). Conclusion: Patients with CKD have a high incidence of pDDIs (mainly mild to moderate). Older age, duration of hospital stays, and polypharmacy all raise the risk of pDDIs. Healthcare professionals (physicians and clinical pharmacist) should use drug interaction checker software programs like Medscape and DDInter to acquire knowledge about different pDDIS and their alternative measures so that the associated adverse drug reactions (ADRs) can be controlled and rational drug combination can be prescribed for management of CKD ensuring better patient care.

ANALYSIS OF ADVERSE DRUG REACTIONS TO ANTIRETROVIRALS USE IN A SECONDARY HOSPITAL

Although antiretrovirals (ARV) evidently extend the life expectancy of people living with HIV/AIDS (PLWH), their associated Adverse Drug Reactions (ADRs) are unavoidable, particularly in long-duration regimens. Several studies have reported a correlation between ADRs and adherence to ARV therapy. Meanwhile, ARV is the main determinant of achieving an immunological and virologic response. Pharmacists play the role of counselors in improving therapeutic outcomes including ADR management. This study aimed to analyze ADRs induced by ARV based on pharmacy documentation and to describe the frequency of PLWH follow-up visits over a two-year period. The study was conducted at Sleman Regional Hospital, an HIV/AIDS referral hospital in Yogyakarta. A cross-sectional design was used with saturated sampling, including all ARV use for HIV/AIDS. Data were collected from the pharmacy unit and patients’ spontaneous reports. Prescribed ARV came from the electronic system, whereas ADR reports were from patients during voluntary consultation with the pharmacist or in PITC services. A total of 110 ARV were administered mostly to male patients aged 25-40 years. The most regimen was tenofovir+lamivudine+efavirenz (91%) with the highest frequency of follow-up visits ? 12 times (53%). The top three ADRs were dizziness (30%), nausea (11%), and headache (8%). Three of the four pediatric patients experienced ADRs, each with AZT-induced fatigue, bloating, and diarrhea in LPV/r monotherapy. Most of the patients did not maintain appointments for hospital visits. Further studies are recommended to analyze the causative factors of non-adherence, including the loss to follow-up group.  Keywords: Adverse Drug Reaction, Antiretroviral, Hospital, Indonesia

Knowledge assessment of radiologists, radiology residents, and radiographers regarding contrast materials and management of adverse drug reactions occurring due to contrast materials: a cross-sectional study.

A questionnaire-based cross-sectional study was conducted from 21 February to 31 March 2019 in five major hospitals of Peshawar, Pakistan. A 30-item questionnaire was adopted from the existing literature containing both open and closed-ended questions and the authors conducted a pilot study among 25 participants to assess the face validity of the tool. A universal sampling technique was adopted. Descriptive statistics were used to summarize the findings of the study. Less than half of the participants could correctly classify iodinated contrast media used in radiology on the basis of ionicity and osmolaity. Sixty-three percent chose severe contrast material-induced allergic reaction as type I hypersensitivity reaction while almost half of them correctly identified the features of iodinated contrast media associated with lesser side effects. Very few of them (6.7%) had read the ACR 2018 manual on contrast media. Regarding the risk factors for acute adverse reactions and signs/symptoms of anaphylaxis few could answer satisfactorily. Twenty-eight percent of participants correctly identified epinephrine as the initial medication in an anaphylactic reaction. Regarding the preferred route of administration, concentration and dose of epinephrine, the participants' correct response was quite poor (43.8%, 6.7%, and 8.6%, respectively). More than 65% of participants could name a single intravenous corticosteroid and antihistamine. Radiology personnel's knowledge regarding contrast material and management of severe contrast material-induced allergic reactions is unsatisfactory.

Interpretable Drug-to-Drug Network Features for Predicting Adverse Drug Reactions.

Recent years have witnessed booming data on drugs and their associated adverse drug reactions (ADRs). It was reported that these ADRs have resulted in a high hospitalisation rate worldwide. Therefore, a tremendous amount of research has been carried out to predict ADRs in the early phases of drug development, with the goal of reducing possible future risks. The pre-clinical and clinical phases of drug research can be time-consuming and cost-ineffective, so academics are looking forward to more extensive data mining and machine learning methods to be applied in this field of study. In this paper, we try to construct a drug-to-drug network based on non-clinical data sources. The network presents underlying relationships between drug pairs according to their common ADRs. Then, multiple node-level and graph-level network features are extracted from this network, e.g., weighted degree centrality, weighted PageRanks, etc. After concatenating the network features to the original drug features, they were fed into seven machine learning models, e.g., logistic regression, random forest, support vector machine, etc., and were compared to the baseline, where there were no network-based features considered. These experiments indicate that all the tested machine-learning methods would benefit from adding these network features. Among all these models, logistic regression (LR) had the highest mean AUROC score (82.1%) across all ADRs tested. Weighted degree centrality and weighted PageRanks were identified to be the most critical network features in the LR classifier. These pieces of evidence strongly indicate that the network approach can be vital in future ADR prediction, and this network-based approach could also be applied to other health informatics datasets.

Assessing Knowledge, Attitude, and Practices towards Ivermectin Pre-exposure Prophylaxis for COVID-19 among Health Care Workers

Background: Health care workers (HCWs) are more likely to be at high risk of SARS-CoV-2 infection due to their direct and/or indirect participation in treatment facilities. Here, we aimed to evaluate the knowledge, attitude, and practices of ivermectin pre-exposure prophylaxis (PEP) in HCWs. Materials and Methods: In this observational study HCWs who were directly/indirectly involved in the medication of COVID-19 patients were selected. The study questionnaire included demographic data; knowledge, attitudes, practices, and associated adverse drug reactions (ADR) after using ivermectin as pre-exposure prophylaxis in COVID-19. Results: The mean age of the selected 306 participants was 34.41 {±standard deviation 4.08}. 66.66% of the participants were men. 15.69% of individuals had co-morbidities. HCWs were about COVID-19, and 94.12% of people know the role of ivermectin as PEP.  Additionally, 180 participants (58.82%) realized that ivermectin can cause adverse drug reactions (ADRs). 70.59% of the study-participants admitted that ivermectin has a protective effect on COVID-19, while 62.75% of the participants believed that the PEP benefits of using ivermectin outweigh the risks. 57.37% (n = 210) of HCW used ivermectin and completed the recommended medication process. Eighteen participants (8.57%) experienced adverse reactions and reported to the ADR monitoring center. Conclusion: 70.59% of the studied participants agreed that ivermectin has a protective effect on COVID-19, and 57.37% of the participants have taken ivermectin as PEP. However, 8.57% of the individuals reported ADR, but none of the participants were severe enough to discontinue the drug.

EVALUATION OF ANTIOXIDANT POTENTIAL AND REDUCING POWER OF CALLUS INDUCED FROM LEAVES OF ASYSTASIA GANGETICA (L.) T.ANDERSON

Objective: Neuropathic pain arises from demage, or pathological changes in the peripheral or central nervous system. The pain is difficult to treat as standard treatment with conventional analgesics doesn`t typically provide effective relief of pain.&#x0D; Methods: It was a one year study of utilization and analysis of prescriptions for PNDs (Painful neuropathic disorders). The parameters evaluated were demographic profile of the patient (age and gender), type and etiology of PNDs, drug data (name of the group of drugs with individual drugs, mono or polytherapy, number of drugs per prescription, formulation) and associated adverse drug reactions (ADR) with the prescribed drug.&#x0D; Results: Maximum number of patients of PNDs resides in the age group of 18 – 35 y (41.2%) &amp; more common in females. The most common PND encountered was painful diabetic neuropathy (43.9%) followed by cervical and lumbar radiculopathy, postherpetic neuralgia. 2942 drugs were prescribed in 1020 prescriptions, out of which 96.8% were oral and 3.2% were topical formulations. Most frequently prescribed group of the drug was tricyclic antidepressants (27.3%) followed by anticonvulsants (25.3%). Polypharmacy was seen 89.7% as compared to monotherapy (10.3%). Only 132 ADRs of various types were seen. The most common organ system affected was central nervous system followed by gastrointestinal systems. The most common drugs implicated for ADRs were TCAs (24.4%), anticonvulsants (16.6%), and Pregabeline (9.8%). There were no fatal adverse events. Mild to moderate ADRs included constipation, nausea, vomiting, drowsiness, dryness of mouth.&#x0D; Conclusion: The choice of drug depends on etiology of neuropathic pain, drug efficacy and availability and also on ADR profile.

PATTERNS OF PRESCRIPTION AND ADR MONITORING OF DRUGS IN THE MANAGEMENT OF NEUROPATHIC PAIN IN A TERTIARY CARE TEACHING HOSPITAL

Objective: Neuropathic pain arises from damage or pathological changes in the peripheral or central nervous system. The pain is difficult to treat as standard treatment with conventional analgesics doesn`t typically provide effective relief of pain.&#x0D; Methods: It was a one-year study of utilization and analysis of prescriptions for PNDs (Painful neuropathic disorders). The parameters evaluated were demographic profile of the patient (age and gender), type and etiology of PNDs, drug data (name of the group of drugs with individual drugs, mono or polytherapy, number of drugs per prescription, formulation) and associated adverse drug reactions (ADR) with the prescribed drug.&#x0D; Results: Maximum number of patients of PNDs resides in the age group of 18 – 35 yrs (41.2%) &amp; more common in females. The most common PND encountered was painful diabetic neuropathy (43.9%) followed by cervical and lumbar radiculopathy, postherpetic neuralgia. 2942 drugs were prescribed in 1020 prescriptions out of which 96.8% were oral and 3.2% were topical formulations. Most frequently prescribed group of the drug was tricyclic antidepressants (27.3%) followed by anticonvulsants (25.3%). Polypharmacy was seen 89.7% as compared to monotherapy (10.3%). Only 132 ADRs of various types were seen. The most common organ system affected was the central nervous system followed by gastro intestinal systems. The most common drugs implicated for ADRs were TCAs (24.4%), anticonvulsants (16.6%), and Pregabeline (9.8%). There were no fatal adverse events. Mild to moderate ADRs included constipation, nausea, vomiting, drowsiness, dryness of mouth.&#x0D; Conclusions: The choice of drug depends on etiology of neuropathic pain, drug efficacy and availability and also on ADR profile.

Occurrences and Outcomes of Immune Checkpoint Inhibitors-Induced Vitiligo in Cancer Patients: A Retrospective Cohort Study.

The use of immune checkpoint inhibitors (ICI) in melanoma and non-small cell lung cancer patients is associated with the onset of vitiligo. However, previous studies have suggested conflicting results on the conditions of occurrence of ICI-induced vitiligo. The aim of this study was to describe the occurrences and outcomes of several cases of ICI-induced vitiligo. A retrospective study was carried out using the French Pharmacovigilance Database (FPD) between the beginning of the commercialization of ICI in France and 1 January 2019, selecting for analysis the vitiligo reactions of patients due to treatment with ICI. Among the 95 case patients identified in the FPD, the median times to onset of vitiligo after the start of pembrolizumab, nivolumab and ipilimumab therapies were 5.4, 5.0, and 3.8months, respectively. Furthermore, 37 patients (45%) discontinued ICI treatment due to disease progression. The median follow-up time of all patients was 33months (interquartile range 2-56). This study provided an overall picture of ICI-induced vitiligo in daily medical practice on a large number of pharmacovigilance observations of case patients. Among the observations of ICI-induced vitiligo, the diagnosed cancer was melanoma for almost all patients. Most patients in the study experienced other associated adverse drug reactions (ADRs), such as colitis, pruritus, hypothyroidism, hyperthyroidism, thyroiditis, pancreatitis, and gastritis. Furthermore, our data suggest that the resolution of pembrolizumab- or nivolumab-induced vitiligo could be a marker of disease progression. Future studies evaluating vitiligo outcomes are warranted.

Clinical impact of pharmacist interventions on improving outcomes in patients receiving immune globulin therapy in a home setting

Background: Immune globulin (IG) therapy is considered a safe and frequently used treatment in a wide range of disease states but has well known associated adverse drug reactions (ADRs) that may be problematic. Patients that receive IG in the home setting may be at higher risk for undertreated ADRs due to the limited number of immediate interventions in the home. Published literature indicate minor reactions are reported in up to 20% of IG infusions and serious ADRs in 2–6%. A pro-active approach to the prevention or reduction of known IG ADRs is critical for these patients. Pharmacists can have the greatest impact on ADRs due to their on-going and regular communication with the patients. Aims: To determine the frequency, type, and severity of ADRs associated with IG infusions and the impact of pharmacist intervention on reducing or eliminating the ADRs. Methods: An ADR Assessment tool was developed to track ADRs reported by patients during or after IG infusions, the severity of the ADR, interventions made by the pharmacist, acceptance of those interventions by the IG prescriber and the outcome of those interventions on reducing or preventing recurrence of the same ADRs. Results: ADRs tracked over a 2-year period show 98% of reported ADRs were mild or moderate in severity having limited impact on the patient’s normal activities. These were all able to be managed at home with simple and readily available therapeutic treatments. After the occurrence of an ADR, pharmacist interventions made to the IG prescriber on future IG infusions had an acceptance of 93%. Pharmacists suggested ADR interventions had a 90% success rate in the total or partial prevention of the same ADR during the next infusion cycle. During this same 2-year period, of the ADRs reported, 0.35% were categorized as serious. Review of these patients and reported serious ADRs showed events that were consistent with the FDA box warnings required on all IG products but did not result in discontinuation of IG therapy in half of these patients. Conclusions: Pharmacists can have a significant impact on preventing or reducing ADRs associated with IG therapy. In addition, the interventions suggested by the pharmacist have a high acceptance rate by prescribers and a positive effect on preventing recurrence of ADRs.

PS1163 PATIENT‐BASED PROSPECTIVE REAL WORLD DATA ANALYSIS SHOWS THAT THE DURATION OF TREATMENT INTERRUPTIONS WITH SUBSEQUENT RESUMPTION OF IDELALISIB THERAPY CAN VARY FROM DAYS TO MONTHS

Background:Idelalisib, a first‐in‐class PI3Kδ‐inhibitor, is licensed in the European Union in relapsed chronic lymphocytic leukemia (CLL) and refractory follicular lymphoma (FL). Treatment should be continued until disease progression or unacceptable toxicity and may continue for several months or years. Optimal therapy management is therefore important and may include temporary treatment interruptions (TIs) and dose modifications to manage idelalisib associated adverse drug reactions (ADRs).Aims:Recent data from a retrospective analysis of idelalisib clinical studies suggest that patients may benefit from optimal ADR management of idelalisib via TI and subsequent resumption of therapy [Ma et al. ASH 2018]. Here we analyzed frequency and duration of TIs within a prospective observational study. To understand the effect of TIs on the course of disease, we additionally analyzed lymphocyte counts during and after treatment interruption on an individual patient level.Methods:Post‐hoc analysis of a prospective, two‐cohort, multicenter, non‐interventional post‐authorization safety study (PASS) reporting real world safety and effectiveness data on the use of idelalisib in Germany. Inclusion of patients was based on the physician's decision to initiate treatment with idelalisib in accordance with the European Summary of Product Characteristics. Detailed methods, patient characteristics and results were already published at two conferences [Hoechstetter et al. DGHO 2018; Hoechstetter et al. ASH 2018]. Descriptive statistics were used for data analysis. Idelalisib TIs were defined as documented interruptions with subsequent resumption of idelalisib therapy.Results:96 patients (84 CLL and 12 FL patients) enrolled at 45 sites were included until data cut in February 2018 with a median follow‐up of 9.7 months. 58 patients had documented permanent discontinuation of idelalisib therapy. 49 patients had one or more documented TIs with 26 patients (one TI n = 20, two TI n = 6) subsequently resuming therapy. After interruptions, treatment was resumed with the standard or a reduced idelalisib dose of 150 mg or 100 mg twice daily, respectively. The most frequently reported reason for both dose reduction and TI was ADR, only 9 TIs followed an adverse event (AE) not related to idelalisib. The 3 most commonly reported ADRs (events) resulting in TI were diarrhea (9), pulmonary complications (4) and rash (3). The duration of TIs varied widely from only a few to 235 days. The median (range) duration of a single TI was 15 (1–235) days, representing 15 (1–86) days for the first and 16 (5–235) days for the second interruption, respectively. 9 patients had a single interruption with a duration of &gt;30 days. Patient level data demonstrate stable or only moderate changes in lymphocyte counts during this treatment interruption.Summary/Conclusion:Optimal management of idelalisib therapy to achieve best outcomes for patients may include temporary TIs and/or dose modifications. However, little information is available about the duration of idelalisib TIs and the possibility to resume therapy in routine clinical practice. Our analysis of prospectively collected real world data shows that the duration of TIs may vary widely from a few days to several months with about 50% of patients with a TI resuming idelalisib therapy. Patient level data suggest that lymphocyte counts were relatively stable during and after TIs. Our results therefore provide evidence that idelalisib treatment may be interrupted to allow treatment of ADRs/AEs with subsequent resumption of idelalisib therapy.image

Pattern Discovery from High-Order Drug-Drug Interaction Relations.

Drug-drug interactions (DDIs) and associated adverse drug reactions (ADRs) represent a significant public health problem in the USA. The research presented in this manuscript tackles the problems of representing, quantifying, discovering, and visualizing patterns from high-order DDIs in a purely data-driven fashion within a unified graph-based framework and via unified convolution-based algorithms. We formulate the problem based on the notions of nondirectional DDI relations (DDI-nd's) and directional DDI relations (DDI-d's), and correspondingly developed weighted complete graphs and hyper-graphlets for their representation, respectively. We also develop a convolutional scheme and its stochastic algorithm to discover DDI-based drug-drug similarities. Our experimental results demonstrate that such approaches can well capture the patterns of high-order DDIs.

Adverse Drug Reactions Associated with Ceftaroline Use: A 2-Center Retrospective Cohort

Ceftaroline fosamil is a cephalosporin approved for treating skin and soft tissue infections (SSTIs), including those caused by methicillin-resistant Staphylococcus aureus and community-acquired pneumonia (CAP). We aimed to study ceftaroline use and associated adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs), among inpatients. We performed a retrospective electronic health record review of inpatients from Massachusetts General Hospital and Brigham and Women's Hospital who received ceftaroline between May 2012 and February 2015. ADRs diagnosed by clinical providers during the course of clinical care were subsequently verified and classified. Risk factors for ADRs were identified. Among 96 patients (median age, 57 years; 54% females) who received a median of 28 (interquartile range, 6-63) ceftaroline doses, 54% were being treated for methicillin-resistant Staphylococcus aureus and treatment indications other than SSTI and CAP comprised 59% of care. There were 31 ADRs observed in 20 (21%) patients; hematologic (n= 15) and cutaneous (n= 9) findings were most common. Observed HSRs included rash with mucosal lesions (n= 1), rash with skin desquamation (n= 1), and possible organ-specific HSRs (n=2). Patients who suffered an ADR received more doses of ceftaroline (median, 46 vs 21; P= .013). There was no increased risk of ceftaroline ADR among patients with reported beta-lactam allergy history (P > .5). Ceftaroline is used to treat a range of infections beyond SSTI and CAP. We observed a high rate of ADRs from ceftaroline, including signs of severe HSRs. More data are needed to understand the frequency and predictors of ceftaroline ADRs and HSRs.

PHS1 - Medication Utilization in incident adverse Drug reactions of Cancer Chemotherapy - a Pharmacist Perspective

To describe the occurrence rates and causality evidence of cancer medication–associated adverse drug reactions (ADRs) and to evaluate Medication Utilization in managing the occurred ADRs. The patient’s data was collected using patient data collection forms in inpatient Radiotherapy department. The ADR assessment is done by using WHO causality assessment scale and Naranjo’s causality assessment scale. In a total of 536 patients, 78% (n=418) experienced adverse drug reactions. Patients with single adverse drug reaction are 43% (n=178) of 418, whereas 23% (n=96) experienced two adverse drug reactions and 9% (n=38) were found to be experiencing more than 2 adverse drug reactions. Alopecia 95% (n=397), Nausea and vomiting 82% (n=343), myelosuppression 42.1% (n=176), Skin pigmentation 15.3% (n=64), itching 11.4% (n=48), Diarrhea 11% (n=46), mucositis 10.2% (n=43), Constipation 6.22% (n=26), cardiotoxicity 2% (n=8) are most commonly observed ADRs. The drugs and their proportions for management of chemotherapy induced adverse drug reactions include Filgrastim (100%), metachlopromide (87.0%), different antibiotics like Piperacillin+Tazobactum (77.8%), Ceftriaxone (73.3%), Ondansetron (70%) and Dulcolax (66.6%). Approximately 78% of patients taking chemotherapy experienced adverse drug reactions that are mostly managed by utilizing proper medications, which further elucidate the opportunity for clinical pharmacists to monitor and manage adverse drug reactions cautiously, thereby minimizing the after effects of chemotherapy and improving the patient’s outcomes.

A Method for Mining Infrequent Causal Associations and Its Application in Finding Adverse Drug Reaction Signal Pairs

In many real-world applications, it is important to mine causal relationships where an event or event pattern causes certain outcomes with low probability. Discovering this kind of causal relationships can help us prevent or correct negative outcomes caused by their antecedents. In this paper, we propose an innovative data mining framework and apply it to mine potential causal associations in electronic patient data sets where the drug-related events of interest occur infrequently. Specifically, we created a novel interestingness measure, exclusive causal-leverage, based on a computational, fuzzy recognition-primed decision (RPD) model that we previously developed. On the basis of this new measure, a data mining algorithm was developed to mine the causal relationship between drugs and their associated adverse drug reactions (ADRs). The algorithm was tested on real patient data retrieved from the Veterans Affairs Medical Center in Detroit, Michigan. The retrieved data included 16,206 patients (15,605 male, 601 female). The exclusive causal-leverage was employed to rank the potential causal associations between each of the three selected drugs (i.e., enalapril, pravastatin, and rosuvastatin) and 3,954 recorded symptoms, each of which corresponded to a potential ADR. The top 10 drug-symptom pairs for each drug were evaluated by the physicians on our project team. The numbers of symptoms considered as likely real ADRs for enalapril, pravastatin, and rosuvastatin were 8, 7, and 6, respectively. These preliminary results indicate the usefulness of our method in finding potential ADR signal pairs for further analysis (e.g., epidemiology study) and investigation (e.g., case review) by drug safety professionals.

Impact of United States Food and Drug Administration's boxed warnings on adverse drug reactions reporting rates and risk mitigation for multiple myeloma drugs

Purpose:To determine the relationship between boxed warnings issuance by the US Food and Drug Administration (FDA) and the proportional reporting rates of the associated adverse drug reactions (ADRs) to the FDA's Adverse Event Reporting System (FAERS) for multiple myeloma (MM) drugs.Methods:We compiled a list of all FDA approved MM drugs and identified their associated ADR boxed warnings, through FDA's website and physician desk reference. Drugs that were issued boxed warnings after their market launch were included in the analysis, i.e., melphalan, thalidomide, vincristine, carmustine and doxorubicin. For each drug/ADR boxed warning combination, we retrieved all reported cases from the FAERS and calculated their Empiric Bayes Geometric Means (EBGMs), in pre- and post-boxed warning periods. Chi-square tests were performed to compare serious adverse drug events before and after boxed warnings for all drug/ADR combinations.Results:A total of 10 drug/ADR boxed warning combinations were identified, of which EBGM signals increased for six combinations after a boxed warning was issued. Reports of serious adverse drug events also increased significantly (p < 0.05).Conclusion:Boxed warnings were associated with increased FAERS reporting, indicating increased awareness of ADRs for MM drugs. Proactive pharmacovigilance programs, such as the FDA's Mini-Sentinel Project, may improve timeliness of detection of rare ADRs.

Results of forty years Yellow Card reporting for commonly used perioperative analgesic drugs

A variety of analgesics are used perioperatively and associated adverse drug reactions (ADRs) may complicate anaesthesia and recovery. We aimed to measure the demographics of reported suspected ADRs to alfentanil, fentanyl, ketorolac, morphine, nalbuphine, papaveretum, pethidine and remifentanil. We report a retrospective analysis of Yellow Card reports of suspected ADRs from 1965-2004 as classified in the Adverse Drug Reaction On-line Tracking database (ADROIT) of the Medicines and Healthcare products Regulatory Agency (MHRA). In total, 1312 reactions were retrieved. A single drug was reported in 908, 39 were fatal and 219 categorised as 'allergic'. Allergic phenomenon varied from 2/33 (6%) for remifentanil to 11/53 (21%) for alfentanil. 'Cardiovascular' reactions were reported frequently with remifentanil (18/33, 55%) and alfentanil (19/53, 36%) and these generated a signal for possible hazards from proportional reporting ratios (PRRs). The opioid fentanyl was associated with similar hazard signals for muscular and psychiatric ADRs. Perioperative vigilance may reduce morbidity and mortality from preventable ADRs to analgesic drugs. Denominator and diagnostic data are essential for prospective studies.

Dissemination of Information on Potentially Fatal Adverse Drug Reactions for Cancer Drugs From 2000 to 2002: First Results From the Research on Adverse Drug Events and Reports Project

To describe the clinical findings, occurrence rates, causality evidence, and dissemination media for serious cancer drug-associated adverse drug reactions (ADRs) reported in the postmarketing setting. ADRs were termed serious if they resulted in death or severe organ failure. ADR information for oncology drugs from package insert (PI) revisions, so-called Dear Doctor letters, and journal articles was evaluated to identify serious ADRs reported from 2000 to 2002. Timing and content of information disseminated was assessed. Twenty-five serious ADRs associated with 22 oncology drugs were identified after approval. Approximately half of these serious ADRs are associated with drugs approved before 1995. ADRs were described in articles in medical journals (17 ADRs), PI revisions (18 ADRs), and Dear Doctor letters (12 ADRs). PI revisions occurred less than 1 year after peer-reviewed publication for four ADRs. These revisions often differed for similar ADRs that occurred with drugs of the same class. Five of the seven ADRs lacking PI changes occurred with off-label use, for which PI change is not recommended by US Food and Drug Administration (FDA) policy. No cancer drug was withdrawn from the market during the observation period. Our findings demonstrate that serious ADRs may be discovered as long as 36 years after a drug receives FDA approval. This suggests a need for continued vigilance and efficient strategies for dissemination of information about ADRs associated with cancer drugs.

Combination Products as First-Line Pharmacotherapy

IN THE COURSE of evaluation for approval, a single-component drug is occasionally found to be unambiguously less effective or more dangerous than others. Such a drug may, nevertheless, be a valuable addition to the armamentarium, but it will be approved only as a second-line therapy, to be used only after others have been found to be ineffective or contraindicated. For example, bepridil is approved for the treatment of chronic stable angina, but its associated adverse drug reactions (ADRs) are sufficiently more severe than those of other approved antianginal products that bepridil is not approved as first-line therapy. Drugs like bepridil are unusual. Most single-component products are approved as first-line therapy. Betaxolol, bisoprolol, chlorthalidone, and hydrochlorothiazide are separately approved as first-line therapy for hypertension, so some physicians may find it unremarkable that fixed-dose combinations of betaxolol and chlorthalidone and of bisoprolol and hydrochlorothiazide are also approved as first-line therapy. In fact,