Serious Adverse Drug Reactions Research Articles

Discovering clinical drug-drug interactions with known pharmacokinetics mechanisms using spontaneous reporting systems and electronic health records

ObjectiveAlthough the mechanisms behind pharmacokinetic (PK) drug-drug interactions (DDIs) are well-documented, bridging the gap between this knowledge and clinical evidence of DDIs, especially for serious adverse drug reactions (SADRs), remains challenging. While leveraging the FDA Adverse Event Reporting System (FAERS) database along with disproportionality analysis tends to detect a vast number of DDI signals, this abundance complicates further investigation, such as validation through clinical trials. Our study proposed a framework to efficiently prioritize these signals and assessed their reliability using multi-source Electronic Health Records (EHR) to identify top candidates for further investigation. MethodsWe analyzed FAERS data spanning from January 2004 to March 2023, employing four established disproportionality methods: Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagating Neural Network (BCPNN). Building upon these models, we developed four ranking models to prioritize DDI-SADR signals and cross-referenced signals with DrugBank. To validate the top-ranked signals, we employed longitudinal EHRs from Vanderbilt University Medical Center and the All of Us research program. The performance of each model was assessed by counting how many of the top-ranked signals were confirmed by EHRs and calculating the average ranking of these confirmed signals. ResultsOut of 189 DDI-SADR signals identified by all four disproportionality methods, only two were documented in the DrugBank database. By prioritizing the top 20 signals as determined by each of the four disproportionality methods and our four ranking models, 58 unique DDI-SADR signals were selected for EHR validations. Of these, five signals were confirmed. The ranking model, which integrated the MGPS and BCPNN, demonstrated superior performance by assigning the highest priority to those five EHR-confirmed signals. ConclusionThe fusion of disproportionality analysis with ranking models, validated through multi-source EHRs, presents a groundbreaking approach to pharmacovigilance. Our study's confirmation of five significant DDI-SADRs, previously unrecorded in the DrugBank database, highlights the essential role of advanced data analysis techniques in identifying ADRs.

The safety and effectiveness of remdesivir in a postmarketing surveillance study in Japan

BackgroundTo evaluate the occurrence of adverse drug reactions (ADRs) and to assess mortality and health status in participants receiving remdesivir in real-world settings in Japan. MethodsThis postmarketing surveillance study used an all-case surveillance method for enrollment. Participants with SARS-CoV-2 infection administered remdesivir from July 2020 to November 2021 in Japan were eligible for inclusion. The observation period was from remdesivir treatment initiation to 4 weeks after the end of treatment or treatment discontinuation. Clinical status and outcomes were analyzed by Kaplan-Meier plots and compared across subgroups at baseline, Day 14, Day 28, and the final observation point. ResultsThe analysis included 2128 participants (mean age, 67 years; 71.4 % male; 84.1 % with current comorbidities). ADRs and serious adverse drug reactions (SADRs) were reported among 10.4 % and 1.2 % participants, respectively. Overall, 191/2127 participants died (mortality rate [95 % confidence interval], 11.10 [9.66–12.75] per 100 person-months), 1511/2127 showed clinical improvement (117.8 [112.0–123.9] per 100 person-months), 1392/2127 recovered (103.9 [98.6–110.0] per 100 person-months), and 216/324 were extubated (107.0 [93.6–122.3] per 100 person-months). ConclusionsThe incidence of ADRs and SADRs was low, and no new safety concerns were identified. Observed mortality and clinical improvement results were consistent with prior studies, confirming remdesivir's benefits in real-world settings in Japan.

Safety and Effectiveness of Ustekinumab for Crohn's Disease in Japanese Post-marketing Surveillance in Biologic-Naive and -Experienced Conriemed.

To present the real-world evidence on the safety and effectiveness of ustekinumab (UST) through 52-week treatment for Crohn's disease (CD) under an analysis of post-market surveillance data in Japan. This prospective, post-marketing surveillance study was conducted in 341 patients from 91 medical facilities in Japan. Patients received UST 90 mg injected subcutaneously once every 12 weeks (or every 8 weeks if patients show weak effectiveness) after an induction dose given intravenously. Clinical response (100-point decrease in Crohn's Disease Activity Index [CDAI] score), clinical remission (CDAI score of <150), steroid-free clinical remission, C-reactive protein, endoscopy, physician global assessment, and adverse drug reactions (ADRs) were evaluated through 52 weeks. The overall rate of clinical remission was 49.2% at week 8 and 56.0% at week 52. The rate of clinical remission in biologic-naive patients was 75.9% and 66.7% at weeks 8 and 52, respectively, whereas the rate in biologic-experienced patients was 41.4% and 52.6% at weeks 8 and 52, respectively. For 52 weeks, the overall incidence of ADRs and serious adverse drug reactions (SADRs) was 11.7% and 6.7%, respectively. The most frequently reported SADRs was worsening of CD (1.8%). In multivariate analysis, ADRs incidence was significantly lower in patients with ileal involvement of CD (odds ratio = 0.25, 95% CI 0.07-0.85, P = .026), although disease location has no association with effectiveness of UST. The present study identified no new safety concerns and effectiveness for CD in Japanese patients treated with UST.

666. Outcomes Using Cefiderocol for the Treatment of Acinetobacter baumannii Infections from the PROVE (Real-World Evidence) Study

Abstract Background PROVE is an ongoing international, retrospective study assessing cefiderocol (CFDC) for Gram-negative (GN) infections. Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are difficult-to-treat with limited treatment options. CFDC is a novel sidero cephalosporin with activity against CRAB. This analysis describes the outcomes and treatment patterns of CFDC treatment in CRAB infections from this study. Methods Patients were eligible if they received ≥ 72 hours of CFDC. Key patient characteristics, infecting pathogen susceptibility, illness severity, and treatment patterns were assessed. Fourteen and 30-day all-cause mortality (ACM) and clinical cure were examined as outcomes. Susceptibility testing was performed locally. Serious adverse drug reactions (SADR) were recorded. Results To date,123 patients treated with CFDC at 12 sites were included. Forty-one had monomicrobial (n=29) or polymicrobial (n=12) Acinetobacter baumannii (AB) infection. All but one were CRAB. The median age was 53 years; 71% were male. The most prevalent comorbidity was severe burns (N=9, 22%). Sixty-one percent of patients received CFDC in the ICU, 51% required mechanical ventilation, and 34% required vasopressor support. The median time from positive culture to CFDC initiation was 5 days. CFDC monotherapy was used in 61%. Tetracyclines were the most common concurrent GN antibiotics used with CFDC (N = 8, 19.5%). Targeted therapy with or without prior GN antibiotics was used in 76%, salvage in 20%, and empirical in 2%. Susceptibility results were available for 28 AB cultures from 28 patients of which 82% were susceptible to CFDC. Post-CFDC 14- and 30-day ACM was 12% (95% CI: 4%-26%) and 22% (95% CI: 11%-38%), respectively. Clinical resolution was achieved in 59% (95% CI: 42% -74%). Thirty-day ACM varied by susceptibility to CFDC: 26% for susceptible, 40% for resistant. One SADR (interstitial nephritis) was reported. Cefiderocol Use Patterns in Acinetobacter baumannii Conclusion Real-world use of CFDC for AB demonstrates that most patients were complex with multiple comorbidities and severe illness prior to treatment. It was used mostly as targeted therapy. CFDC may be a treatment option in these difficult-to-treat infections. Disclosures Stephen Marcella, MD, MPH, Shionogi: Shionogi employee|Shionogi, Inc: Employee Amy L. Carr, PharmD, BCIDP, Shionogi: Advisory Board Benjamin Georgiades, PharmD, Shionogi, Inc: Employee Caroline Margiotta, MA, Shionogi, Inc: contracting work for Shionogi, Inc.

667. Real-world Experience of Cefiderocol with Pseudomonas aeruginosa in the PROVE (Retrospective Cefiderocol Chart Review) Study

Abstract Background Gram-negative (GN) bacterial resistance is an urgent global health problem. Cefiderocol (CFDC) is active against many resistant GN pathogens, including Pseudomonas aeruginosa (PA). PROVE is an ongoing international, retrospective study assessment of CFDC use for Gram-negative infections (GNI). Methods Patients were eligible if they received ≥ 72 hours of CFDC. Patient and pathogen characteristics, hospital course, and antibiotic treatment patterns were described. All-cause mortality (ACM) at 14 and 30 days and clinical cure were examined as outcomes, overall, and by key characteristics such as pathogen susceptibility (determined at the local level), patient demographics, infection site, and severity of illness. Serious adverse drug reactions (SADR) were recorded. Results To date, 123 patients treated with CFDC at 12 sites were included. Sixty-five patients had PA as a pathogen, either alone (N=45) or in combination with another pathogen (N=20) attributed to starting CFDC. The median age was 54 years; 68% were male. The most prevalent comorbidity was diabetes with end stage organ damage (N=15, 23%). CFDC was given in an ICU setting in 54 (82%) patients. Vasopressors and mechanical ventilation were required in 42% and 62%, respectively. Most (91%) PA were carbapenem resistant. The median time from a positive culture to start of CFDC was 6 days. CFDC monotherapy was used in 75%. The most common GN antibiotic class used concurrently with CFDC was aminoglycosides (N=7). Targeted therapy with CFDC against pathogens of known susceptibility with or without prior GN antibiotics accounted for 80% of use. The remainder was used for salvage (15%) or empirically (2%). Susceptibility testing to CFDC, available for 54 cultures (54 patients), showed 94% (51/54) were susceptible. Post-CFDC initiation 14- and 30-day all-cause mortality (ACM) was 9% (95% CI: 3%-19%) and 23% (95% CI: 14%-35%) respectively. Clinical resolution was achieved in 66% (95% CI: 53% -77%). Thirty-day ACM for susceptible pathogens was 25% (13/51). Cefiderocol Use Patterns in Pseudomonas aeruginosa Conclusion Real-world use of CFDC for PA demonstrated that most patients had multiple comorbidities and were severely ill. These data suggest that CFDC is being used appropriately with little empirical use in patients with few treatment options. Disclosures Stephen Marcella, MD, MPH, Shionogi: Shionogi employee|Shionogi, Inc: Employee Amy L. Carr, PharmD, BCIDP, Shionogi: Advisory Board Sean Nguyen, n/a, Shionogi: Employee Anan Zhou, MPH, Shionogi, Inc: contracting work for Shionogi, Inc.

A Retrospective Assessment of The Safety Profile of Pioglitazone in T2dm Patients

Background: Pioglitazone is a drug that belongs to the category of thiazolidinedione (TZD) and is used for its hypoglycemic activity that is very-well associated with some serious adverse drug reactions (ADR). Previous studies have dealt with country-specific pharmacovigilance databases to assess the ADR profile of pioglitazone but none of them utilized a scholarly literature database. &#x0D; Objective: This study was conducted to assess the safety profile of pioglitazone in terms of expectedness, causality, and the seriousness of ADR by using a literature database.&#x0D; Methods: The published literature cases of pioglitazone-induced ADR from the PubMed database (between 1993 and 2020) were retrieved by using Medical Subject Headings (MeSH) terms.Only the valid cases (as per the ICH validity criteria) were analyzed. Following this, valid cases were further assessed for the expectedness of ADR by using the "Summary of Product Characteristics" document of Takeda Pharmaceuticals UK Ltd. Seriousness criteria of WHO for ADR were used for assessing the seriousness of ADR while the Naranjo’s scale was used for causality assessment.&#x0D; Results: A total of 871 results were found of which only 26 valid ICSRs cases were found. Of the total 168 ADRs, a total of 131 (77.97%) and 37 (22.02%) unexpected and expected ADRs were found. Only two of the events were found to be non-serious and they were Iatrogenic lipomatosis and Angioneurotic edema. 1 (32.5 %), 24 (77.4 %), 6 (19.35 %) reactions were serious due to death, important medical event, and hospitalization, respectively. There were, in total, 7 (27 %) and 19 (74 %) cases that belonged to a possible and probable category, respectively.&#x0D; Conclusion: It is worth mentioning that pioglitazone is associated with the risk of heart failure and edema besides causing bladder cancer. The patient should be evaluated for the possible adverse effects of proper monitoring and follow-ups.&#x0D;

FC 124: Real-World Use of Once-Weekly Semaglutide by Baseline Estimated Glomerular Filtration Rate—A Post-Hoc Analysis of Pooled Data From the Sure Studies (Canada, Denmark/Sweden, Switzerland and UK)

Abstract BACKGROUND AND AIMS The SURE programme of observational real-world studies is investigating once-weekly (OW) subcutaneous semaglutide in routine clinical practice across a diverse type 2 diabetes (T2D) patient population, including those with chronic kidney disease. This pooled post-hoc analysis of SURE Canada, Denmark/Sweden, Switzerland and UK evaluated OW semaglutide use and outcomes according to kidney function at semaglutide initiation. METHOD The SURE studies (all ∼30 weeks’ duration) enrolled adults (≥18 years) with T2D who received OW semaglutide and other anti-hyperglycaemic drugs prescribed at physician discretion; pooled data were analysed to determine change from baseline to end of study (EOS) in HbA1c and body weight (BW) by estimated glomerular function rate (eGFR) subgroups (&amp;lt;30, 30 to &amp;lt;45, 45 to &amp;lt;60, 60 to &amp;lt;90, and ≥90 mL/min/1.73 m2). Safety outcomes were assessed; only serious adverse drug reactions (SADRs) were systematically recorded. RESULTS Data from 913 patients with median (interquartile range) age of 61 (54–68) years and T2D duration of 11.0 (6.2–17.2) years were included. Patients with eGFR &amp;lt;45 mL/min/1.73 m2 were more likely to be older with longer T2D duration than those with eGFR ≥45 mL/min/1.73 m2. Patients with low eGFR were more likely to be receiving insulin at baseline than those in higher eGFR subgroups. At EOS, there were significant reductions in HbA1c and BW in all subgroups with eGFR ≥30 mL/min/1.73 m2 (P &amp;lt;0.0001; Figure 1). The rates of SADRs and adverse events leading to treatment discontinuation were low across all eGFR subgroups (≤0.3% and ≤1.8%, respectively). Overall, 50/72 patients who experienced more than or equal to severe or documented hypoglycaemic episode were receiving insulin at baseline. CONCLUSION OW semaglutide provided clinically relevant glycaemic control and BW improvements, and was well tolerated, in patients with varying degrees of kidney impairment at treatment initiation in a real-world setting. These findings support semaglutide use in routine clinical practice regardless of patients’ kidney function.

Spontaneous Reporting Method Used for Safety Evaluation of Nonsteroidal Anti-Inflammatory Drugs and Paracetamol Products, Based on Assessment of Data from Periodic Reports

High rates of adverse drug reactions (ADRs) associated with nonsteroidal anti-inflammatory drugs (NSAIDs), as well as their irrational and uncontrolled use for self-medication require continuous updating of information on safety profiles of these products.The aim of the study was to assess the reporting rate, frequency, and severity of ADRs to NSAIDs and paracetamol products, based on data from periodic safety update reports (PSURs) submitted to the autonomous non-profit organisation “National Pharmacovigilance Research Centre”.Materials and methods: the study covered 104 PSURs for NSAIDs and paracetamol products. Consumption levels were calculated in patient days (PTDs) and patient years (PTYs) for each international nonproprietary name (INN). The authors also analysed clinical manifestations and severity of ADRs.Results: the total number of PTDs and PTYs for all NSAIDs and paracetamol products, including combination medicines, was 1 963 750 485 PTDs or 5 380 138.3 PTYs, respectively. The PSURs reported 459 ADRs, of which 304 (66.2%) were serious ADRs (SADRs). The comparative analysis of ADR frequencies, expressed as the “ADR/PTY” ratio, for individual products, helped to identify INNs with the highest reporting rates.Conclusions: high ADR/PTY and SADR/PTY values indicating better ADR reporting for some INNs, were observed for piroxicam, paracetamol, dexketoprofen, and ketoprofen, while the lowest values were observed for the “acetyl salicylic acid+caffeine+paracetamol” combination, acetylsalicylic acid, and phenylbutazone. Thus, the comparison of ADR/PTY and SADR/PTY ratios can be recommended as an inclusive approach both for analysis of reporting trends for individual products and for comparison of reporting rates of different medicinal products.

Real-World Safety and Efficacy of Glycopyrronium Bromide in Japanese Patients with COPD: A 52-Week Post-Marketing Surveillance.

To evaluate the long-term safety and efficacy of glycopyrronium (GLY) in patients with COPD in a real-world setting in Japan. This 52-week, multicentre, post-marketing surveillance conducted in Japan, between February 2013 and August 2019, included patients using GLY for the first time for the relief of airway obstructive disorder-related symptoms. Safety outcomes included incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), serious ADRs (SADRs) and priority variables included cardiovascular/cerebrovascular (CCV) AEs and anticholinergic AEs during the 52-week period. Safety outcomes were also assessed in elderly patients. Efficacy outcomes included physician's global assessment, COPD assessment test (CAT) and lung function test. Of the 1,331 patients registered for this surveillance, safety and efficacy outcomes were evaluated in 1,277 patients. In the safety analysis population, the incidence of AEs was 15.51%, SAEs 4.70%, ADRs 5.01% and SADRs 0.31%. The CCV AEs and anticholinergic AEs were reported by 0.70% and 2.58% patients, respectively. Physician's global assessment showed that the overall response rate at the last assessment was 70%. The mean (95% CI) CAT scores decreased from the start of treatment to Week 52 with GLY, (-6.2 [-7.0 to -5.4]). Lung function in terms of trough FEV1 and FVC improved over time from the start of GLY to Week 52. GLY demonstrated an acceptable long-term safety profile with no new safety concerns in a real-life setting. It demonstrated improvement in lung function and symptom control in Japanese COPD patients.

High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial

High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. The aim of this study was to assess the safety and efficacy of high-dose ivermectin in reducing viral load in individuals with early SARS-CoV-2 infection. This was a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Participants were adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection. Exclusion criteria were: pregnant or lactating women; CNS disease; dialysis; severe medical condition with prognosis <6 months; warfarin treatment; and antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned (ratio 1:1:1) according to a randomised permuted block procedure to one of the following arms: placebo (arm A); single-dose ivermectin 600 μg/kg plus placebo for 5 days (arm B); and single-dose ivermectin 1200 μg/kg for 5 days (arm C). Primary outcomes were serious adverse drug reactions (SADRs) and change in viral load at Day 7. From 31 July 2020 to 26 May 2021, 32 participants were randomised to arm A, 29 to arm B and 32 to arm C. Recruitment was stopped on 10 June because of a dramatic drop in cases. The safety analysis included 89 participants and the change in viral load was calculated in 87 participants. No SADRs were registered. Mean (S.D.) log10 viral load reduction was 2.9 (1.6) in arm C, 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (P = 0.099 and 0.122 for C vs. A and B vs. A, respectively). High-dose ivermectin was safe but did not show efficacy to reduce viral load.

Characterisation of seriousness and outcome of adverse drug reactions in patients received cancer chemotherapy drugs – A prospective observational study

Background: Cancer chemotherapeutic drugs are commonly associated with serious adverse effect which contributes to increase in the duration of hospitalisation and economic burden. Aim: The aim of this study was to characterise the seriousness and outcome of adverse drug reactions (ADRs) produced by chemotherapy drugs in cancer patients.Materials and Methods: Patient''s demographic characteristics and ADRs due to chemotherapeutic drugs were documented inpatient case report form. Frequencies of the seriousness of the ADRs, its outcome and preventability were studied using descriptive statistics. Proportion of life-threatening ADRs and ADRs linked to increase in duration of hospitalisation were studied. Factors associated with serious ADRs and patient characteristics were studied using calculation of odds ratio (OR) at 95% confidence interval (P < 0.5).Results: A total of 412 ADRs were noted in selected 120 patients received chemotherapy drugs. Majority of ADRs (61%) were linked to increase in duration of hospital admission. Some ADRs (12%) were noted as life-threatening to the patients. OR 1.58 was found on the association between patient age group and serious ADRs (P = 0.02). Association of preventability of ADRs and serious ADRs shows OR of 3.65 (P = 0.0001). Common serious ADRs were noted as anaemia, neutropenia, fever, thrombocytopenia, diarrhoea, mucositis and nausea and vomiting.Conclusion: The incidence of serious ADRs due to chemotherapy drugs amongst cancer patients is high. Studies on the nature of seriousness of ADRs, outcome and its triggering factors may help to prevent them. Early identification of serious ADRs may support to reduce hospital stay and economic burden.

The severity of adverse drug reactions and their influencing factors based on the ADR monitoring center of Henan Province

Adverse drug reactions (ADRs) may be a serious public health problem and have received widespread attention in recent years. This study has analyzed the factors leading to the occurrence of serious ADRs (SADRs), determined the factors affecting the prognosis of patients with severe adverse reactions at different levels of medical institutions, and finally made corresponding recommendations for the monitoring, prevention, and treatment of SADRs. We used descriptive analysis and chi-square test to analyze the year, age, gender, proportion of SADRs, and the results of the ADRs in the report. Use the logistic regression to analyze the factors affecting the prognosis of SADRs in different levels of medical institutions. A total of 387 642 people’s 394 037 ADRs were collected from the Henan Provincial Adverse Drug Reaction Monitoring Center from 2016 to 2020. Among them 35 742 cases of serious ADRs (9.1%), 96.1% were eventually relieved or cured, but 39 cases of SADRs caused death. The main causes of death included hemorrhages, organ failure, and allergies. Age, number of medication and illnesses, level of medical institution, history of adverse reactions, and type and method of medication were all factors that affected the severity of ADR. The prognosis of SADRs is worse than normal ADRs. The ADRs in autumn and winter and new adverse reactions are unique risk factors found in this study. The elderly and patients with multiple diseases or taking multiple drugs should pay attention to their adverse reactions. They should be closely observed within a week after taking the medicine. The supervision of patients with a history of allergies and new adverse reactions should be strengthened by primary medical institutions, and in nonprimary medical institutions should paid attention with past medical histories, and use imported drugs and biological agents with caution to ensure the safety and health of patients.

Rapid Rate Intravenous Immunoglobulin Administration: Safety Outcomes in 11,334 Infusions

A national home infusion services provider (KabaFusion, LLC) traditionally administered intravenous immunoglobulin (IVIG) at conservative maximum infusion rates to minimize adverse drug reactions (ADRs). The objective of this retrospective observational study was to identify the impact of increased on-label infusion rates of a specific, high-purity product (Octagam) on patient safety. The study included all patients who received IVIG over a 10-year period. The study population was composed of both adult and pediatric patients, with neuroimmune, neuromuscular disorders, and primary immune deficiency diseases warranting IVIG treatment. Patients were divided into two randomized groups to provide an even distribution for analysis: those who received IVIG infusions at a rate of &lt;110 mL/hr (Group 1) and those who received IVIG at ³110 mL/hr (Group 2). There were 489 patients identified for inclusion in Group 1 (n=245) and Group 2 (n=244). Demographics (gender, age) and exposure (number of infusions) were similar between both groups.&#x0D; &#x0D; The study data included 11,334 total IVIG infusions with a total of 392 ADRs (3.5%). ADRs in the high infusion rate group (Group 2) were significantly lower (5.1% vs.1.8%, p&lt;0.0001). In addition, the incidence of non-serious ADRs in Group 2 (1.7%) vs. Group 1 (4.8%) were also significantly lower in the high infusion rate group (p&lt;0.0001). The number of serious adverse drug reactions (SADRs) was lower in Group 2 but did not reach statistical significance (Group 1: 0.3% vs Group 2:0.1%, p=0.0741). Based on these results, infusion rates of specific high-purity IVIG products were associated with statistically and clinically significant lower non serious ADRs in both the adult and pediatric populations, in addition to having an association of clinical significance in both for SADRs. These results can be of great utility in clinical application if applied within the manufacturer’s recommended guidelines, to ease the burden of time required for patients undergoing IVIG infusions.

Safety and effectiveness of ustekinumab in Crohn's disease: Interim results of post-marketing surveillance in Japan.

Background and AimUstekinumab, a human anti‐interleukin‐12/23 monoclonal antibody, has been approved in Japan for the treatment of Crohn's disease. Here, we report the findings from an 8‐week interim analysis of post‐marketing surveillance to evaluate the safety and effectiveness of ustekinumab in Japanese patients with Crohn's disease.MethodsPatients initiating ustekinumab treatment were prospectively evaluated from May 2017 to June 2020 at 91 medical centers in Japan. Adverse drug reactions (ADRs) and serious ADRs (SADRs) were monitored. Effectiveness was evaluated by clinical response, clinical remission, and changes in Crohn's Disease Activity Index (CDAI) and C‐reactive protein (CRP) from baseline to week 8. Presence of perianal disease was documented at baseline and week 8.ResultsIn total, 341 patients were enrolled in the study, of which 339 were included in the safety analysis while 334 were included in the effectiveness analysis. The overall incidences of ADRs and SADRs were 5.3% and 2.1%, respectively. Worsening of Crohn's disease was the most common event. The clinical response and clinical remission rate at week 8 were 40.0% and 48.5%, respectively. Significant improvements in CDAI and serum CRP (P < 0.001) were observed at week 8. CDAI decreased significantly (mean difference: −31.4; 95% confidence interval: −61.1, −1.7; P = 0.038) in biologics‐naïve patients versus patients who had received two or more biologics.ConclusionsThis 8‐week interim analysis of the real‐world study confirmed the effectiveness of ustekinumab‐based therapy in Japanese patients with Crohn's disease. No new safety concerns were found during 8‐week induction period in the Japanese clinical settings.

Off-Label Use and Safety of Drug Use in Vascular Anomalies

Background: Off-label drug use is associated with an increased risk of adverse drug reactions. It is common in pediatrics and in rare diseases, which are two characteristics applying to vascular anomalies (VA). Objectives: The aim of this work was to quantify off-label drug use in VA and assess its safety. Methods: A review was conducted to extract a list of drugs used in VA management. A drug was considered to have significant safety concerns if a black box warning was present or if a serious adverse drug reaction (SADR) was reported in at least 1% of the patients (SADR is defined as a noxious and unintended response to a drug that occurs at any dose and results in hospitalization, prolongation of existing hospitalization, congenital malformation, persistent or significant disability or incapacity, life-threatening condition, or death). The labelling status and safety of each drug was assessed based on the product monograph, Micromedex, and the FDA data. Results: We found that 98.9% of the inventoried drugs were used off-label or unlicensed for VA management. Only the oral solution of propranolol hydrochloride (Hemangeol®) for the treatment of infantile hemangiomas is approved. Significant safety issues concerned 73% of the drugs and were more frequent among systemic than locally delivered drugs. Conclusions: Off-label drug use in VA is the rule and not the exception. Significant safety concerns are common. It is necessary to carefully weigh risk and benefits for every patient when using systemic and local treatments carrying safety concerns. Patients should be openly informed and involved in the decision-making process.

Spontaneous Reports of Serious Adverse Drug Reactions Resulting From Drug-Drug Interactions: An Analysis From the French Pharmacovigilance Database.

Few data are available on the clinical impact of drug–drug interactions (DDIs). Most of the studies are limited to the analysis of exposure to potential DDI or the targeted impact of the combination of a few drugs or therapeutic classes. The analysis of adverse drug reaction (ADR) reports could be a mean to study generally the adverse effects identified due to a DDI. Our objective was to describe the characteristics of ADRs resulting from DDIs reported to the French Pharmacovigilance system and to identify the drugs most often implicated in these ADRs. Considering all ADR reports from January 01, 2012, to December 31, 2016, we identified all cases of ADR resulting from a DDI (DDI-ADRs). We then described these in terms of patients’ characteristics, ADR seriousness, drugs involved (two or more per case), and ADR type. Of the 4,027 reports relating to DDI-ADRs, 3,303 were related to serious ADRs. Patients with serious DDI-ADRs had a median age of 76 years (interquartile range: 63–84); 53% were male. Of all serious DDI-ADRs, 11% were life-threatening and 8% fatal. In 36% of cases, the DDI causing the ADR involved at least three drugs. Overall, 8,424 different drugs were mentioned in the 3,303 serious DDI-ADRs considered. Altogether, drugs from the “antithrombotic agents” subgroup were incriminated in 34% of serious DDI-ADRs. Antidepressants were the second most represented therapeutic/pharmacological subgroup (5% of serious DDI-ADRs). Among the 3,843 ADR types reported in the 3,303 serious DDI-ADRs considered, the most frequently represented were hemorrhage (40% clinical hemorrhage; 6% biological hemorrhage), renal failure (8%), pharmacokinetic alteration (5%), and cardiac arrhythmias (4%). Hemorrhagic accidents are still an important part of serious ADRs resulting from DDIs reported in France. The other clinical consequences of DDIs seem less well identified by pharmacovigilance. Moreover, more than one-third of serious DDI-ADRs involved at least three drugs.

Comparison of Prospective and Retrospective Methods of a Tigecycline Post-Marketing Surveillance Study in the Safety Outcomes of Patients with Complicated Skin Structure Infection, Complicated Intraabdominal Infection and Community-Acquired Pneumonia.

IntroductionSafety data can be collected through prospective and retrospective methods during post-marketing surveillance (PMS). This study aimed to compare prospective and retrospective methods in terms of examining safety data from PMS of tigecycline.MethodsThis PMS study was an open-label, noncomparative, observational, noninterventional and multicenter study of patients who received tigecycline for infections. From July 2007 to April 2015, 3172 patients were included in this study, of which 738 were enrolled prospectively and 2434 retrospectively. To reduce selection bias, demographic and baseline characteristics were adjusted using 1:2 propensity score matching.ResultsAfter propensity score matching, data from 1446 patients were analyzed. The incidences of adverse events (AEs) and serious AEs (SAEs) were determined to be significantly higher in the prospective method compared with those of the retrospective method (P < 0.001 and P = 0.004, respectively). However, no significant differences in the incidences of adverse drug reactions (ADRs) and serious ADRs (SADRs) were detected between the two groups (P = 0.09 and P = 0.33, respectively). In a subgroup analysis of 360 patients from 14 hospitals involved in both prospective and retrospective methods, the incidence of AEs was found to be significantly higher using the prospective method compared with when the retrospective method was used (P < 0.001), but there were no significant differences in ADRs (P = 0.14), SAEs (P = 0.24) and SADRs.ConclusionIn general, the prospective method can detect safety data effectively in a PMS study, whereas retrospective data collection may be an alternative option in collecting ADR data when a prospective PMS study is not deemed feasible.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00398-7.

High Dose Ivermectin for the Early Treatment of COVID-19 (COVIER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial

Background: High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. Aim of this study was to assess safety and efficacy of high-dose ivermectin in reducing viral load in individuals with initial SARS-CoV-2 infection. Methods: Randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial performed in outpatients in Italy. Participants: adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection, providing informed consent. Exclusion criteria: pregnant or lactating women; CNS diseases; participants under dialysis; severe medical condition with prognosis Findings. From 31th July, 2020 to 26th May, 2021, 32 participants were randomized to arm A, 29 to arm B and 32 to arm C. The recruitment was stopped on 10th June, because of a dramatic drop of cases. Eighty-nine participants were included in the safety analysis set, the change in viral load was calculated on 87 participants. No SADR were registered. The mean log10 viral load reduction was 2.9 in arm C (SD 1.6), 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (p=0.099 and 0.122 for C versus A and B versus A, respectively). Interpretation: High- dose ivermectin demonstrated safe, but did not prove efficacy to reduce viral load.Trial Registration: The protocol was registered with ClinicalTrials.gov , NCT04438850. Funding: The trial was partly funded by the Italian Ministry of Health.Declaration of Interest: None to declare. Ethical Approval: This study was approved by the national Ethics Committee of INMI – Spallanzani in Rome that is competent for all COVID-19 trials in Italy (resolution 139/2020 of 28th May, 2020), and by the Italian drug agency AIFA (resolution 136BIS/2020 of 18th May, 2020).

Knowledge, attitude, and practice regarding pharmacovigilance among the general public in Western China: a cross-sectional study

Objectives Spontaneous reporting of adverse drug reactions (ADRs) to pharmacovigilance centers is a common and inexpensive method of ADR detection. Although China requires patients to report ADRs directly, the reporting rate is extremely low. We assessed public knowledge, attitudes, and practice (KAP) regarding pharmacovigilance in Shaanxi Province, China. Methods A self-administered questionnaire to evaluate the KAP of the general public regarding pharmacovigilance was designed and distributed in selected locations throughout Xi’an. The data were double input and statistical methods were used to analyze questionnaire responses. Results Knowledge scores among consumers regarding pharmacovigilance was low. Women and respondents in younger age groups had high knowledge scores. Over 85.0% of respondents had a positive attitude toward ADR monitoring. Most respondents said they would voluntarily report ADR to medical personnel, and 85.1% said they would report ADRs with easier policies. Further, 89.1% of respondents preferred reporting ADRs by phone or online whereas 10.9% preferred email or post. Regarding reasons for not reporting ADRs, 57.8 and 43.6% of respondents, respectively, did not know to whom to give feedback and felt that ADRs were not serious enough to report. Respondents had difficulty with portions of the ADR reporting form addressing drug information and description of ADR signals. Conclusions The public has poor awareness about, but a positive attitude toward, pharmacovigilance. Unclear feedback pathways and lack of understanding about the seriousness of ADRs were the main reasons patients did not report ADRs, and respondents had difficulty with parts of the reporting form. The government should publicize the importance of ADR monitoring and develop more suitable forms and measures for patients to report ADR.

Real-world safety and effectiveness of ledipasvir/sofosbuvir for the treatment of chronic hepatitis C virus genotype 1 in Japan.

As patients with chronic hepatitis C virus (HCV) tend to be older and/or have advanced liver disease in Japan, real-world data are needed to evaluate safe and effective treatment options. The study aim was to assess safety and effectiveness of ledipasvir/sofosbuvir (LDV/SOF) in a real-world cohort of Japanese patients with HCV genotype (GT) 1 infection overall and by patient subgroups: elderly, compensated cirrhotic, advanced fibrotic and those with hepatocellular carcinoma (HCC). A large prospective observational study was conducted, enrolling adult patients treated for HCV GT1 infection with LDV/SOF at clinical sites across Japan. Patients were observed for safety outcomes during and 4weeks after treatment, and for sustained virologic response at 12-weeks post-treatment (SVR12). Incidence rates (IRs) of adverse drug reactions (ADRs) and serious ADRs (SADRs) and SVR12 rates were assessed overall and by subgroups. ADR and SADR IRs were low (2.26 and 0.17 per 100 person-months, respectively) and did not significantly differ in elderly patients or those with presence of compensated cirrhosis, worsening fibrosis or HCC. SVR12 rates were high overall (98.5%) and across subgroups investigated (≥94%), including patients who were elderly (98.2%), treatment-experienced (97.6%), advanced fibrotic (≥95.8%), had existing NS5A resistance-associated substitutions reported pre-treatment (95.0%), compensated cirrhosis (95.7%), HCC (94.0%) and other chronic liver diseases (96.1%). In this large, real-world observational study of Japanese patients with HCV GT1 infection, LDV/SOF treatment resulted in low incidence of adverse events, with high real-world effectiveness, even among patients with potentially higher risks of adverse safety outcomes and treatment failure.