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Biosimilars provide the possibility to reduce the high expenditure on biologic drugs and expand access to effective but less expensive treatments. Biosimilars of trastuzumab showed significant cost savings from the payer's perspective in the USA and Europe. After 2020, with the first approval of a trastuzumab biosimilar in China, it became feasible for biosimilar switching for trastuzumab. However, the economic impact of switching to a trastuzumab biosimilar was not evaluated. A budget impact model was constructed from a payer's perspective of China to demonstrate the economic impact of the introduction of a biosimilar trastuzumab in the treatment of human epidermal growth factor receptor 2-positive breast cancer.This budget impact model was based on disease incidence to estimate the net budget impact using epidemiological data from the literature, financial reports from manufacturers on the market shares of originator trastuzumab (HerceptinAnalyses of the base-case and scenario results implied that adoption of a trastuzumab biosimilar would lead to an expenditure decrease. The average total cost savings over 5 years was estimated to be US$46,651,348, with a range from $10,306,611 in year 1 to $60,821,822 in year 5. The cost savings could benefit an additional 654-3858 patients with breast cancer. If utilizing costs from real-world practice, the introduction of a trastuzumab biosimilar could help an additional 2237-13,203 patients get access to human epidermal growth factor receptor 2-positive targeted therapy. When volume-based procurement was carried out after year 4, $672,366,180 could be saved annually.This budget impact analysis emphasized the positive effects of adopting a trastuzumab biosimilar in the healthcare system of China. However, cost savings still have a large potential to decrease by regulating pricing and by the procurement policy of biosimilars.

Lamivudine is a first-line medication used for human immunodeficiency virus (HIV) treatment. To date, the population pharmacokinetics of lamivudine in Chinese HIV-infected adults have not been assessed. This study aimed to develop a population pharmacokinetic model for oral lamivudine in Chinese HIV-infected adults and to determine the optimal lamivudine dosage regimens. A total of 1113 samples, from 828 Chinese HIV-infected patients treated with lamivudine 300 mg every 24 hours, were pooled from two open-label, prospective clinical trials. A population pharmacokinetics analysis was performed using a nonlinear mixed-effects modeling method. A Monte Carlo simulation was conducted to optimize lamivudine dosing. A two-compartment model adequately described the population pharmacokinetics of lamivudine. The typical population estimate for apparent clearance was 28.3 L/h. Creatinine clearance was identified as a significant factor influencing apparent clearance. According to the Monte Carlo simulation, patients with creatinine clearance between 50 and 70 mL/min should receive lamivudine 200 mg every 24 h or 300 mg every 36 h, to achieve optimal lamivudine exposure. No obvious ethnic differences were observed in lamivudine pharmacokinetics between Chinese and Caucasian populations. Additionally, a model-informed dosage regimen is recommended for patients with impaired renal function.

Background Concurrent use of dronedarone and oral anti-coagulants are common since both classes of medications are essential to atrial fibrillation (AF) management. Dronedarone is a moderate inhibitor of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). All direct oral anticoagulants (DOACs) are P-gp substrates, and apixaban and rivaroxaban are in addition metabolized by CYP3A4. The current study aims to investigate the impact of dronedarone co-administration on exposure as well as bleeding risk of apixaban or rivaroxaban with physiologically based pharmacokinetic (PBPK) modeling. Method Modeling and simulation were conducted with Simcyp® Simulator. The input parameters required for dronedarone modeling were collected from literature. The developed dronedarone PBPK model was extensively validated with reported DDIs between dronedarone and CYP3A4 and P-gp substrates. After model validation, the model was applied to evaluate DDI potential of dronedarone on exposure and consequent increase in major bleeding risk of apixaban or rivaroxaban in both healthy subjects and AF patients with renal impairment. Result The developed PBPK models accurately describe dronedarone pharmacokinetics following single- oral dose in healthy subjects. The model also predicts DDIs between dronedarone and CYP3A4 and P-gp substrates well, with all fold errors less than 1.5. Co-administration of dronedarone would lead to a 1.23-fold increase and a 1.36-fold increase in AUC24h for rivaroxaban and apixaban in healthy subjects, respectively. In addition, patients with moderate and severe renal impairment co-administered with dronedarone and apixaban would have 1.78-fold and 1.89-fold increase of major bleeding risk, respectively. In contrast, while dronedarone would also increase exposure of rivaroxban in patients with moderate and severe renal impairment, increases in major bleeding risk were 1.18-fold and 1.3-fold, respectively.. Conclusions Dronedarone co-administration would increase major bleeding risks of rivaroxban and apixban. Reduced apixaban dosing regimen of 3.75mg q12h was recommended when dronedarone is co-administered, for AF patients with both normal and impaired renal functions. Reduced rivaroxban dosing regimen of 10mg q24h was recommended when dronedarone is co-administered for AF patients with both moderate and severe impaired renal functions.

BackgroundConcurrent use of dronedarone and oral anti-coagulants are common since both classes of medications are essential to atrial fibrillation management. Dronedarone is a moderate inhibitor of CYP3A4 and P-glycoprotein (P-gp). To date, no drug-drug interaction (DDI) studies between dronedarone and apixaban or rivaroxaban were reported. The current study aims to study the impact of dronedarone co-administration on exposure of apixaban or rivaroxaban with physiologically based pharmacokinetic (PBPK) modeling.MethodModeling and simulation were conducted with Simcyp Simulator. The input parameters required for dronedarone modeling were obtained from literature. The developed dronedarone PBPK model was extensively validated with reported DDIs between dronedarone and CYP3A4 and P-gp substrates. After model validation, the model was applied to evaluate DDI potential of dronedarone on exposure of apixaban or rivaroxaban in both healthy population and patients with renal impairment.ResultThe developed PBPK models accurately describe dronedarone pharmacokinetics following single-dose oral administration in healthy volunteers. The model also predicts DDIs between dronedarone and CYP3A4 and P-gp substrates well, with all fold errors less than 1.5. The AUC of apixaban was increased by 1.36-fold in healthy population due to dronedarone co-administration. In addition, for patients with moderate renal impairment, the AUC of apixaban and rivaroxaban would increase by 1.38-fold and 1.25-fold, respectively.ConclusionsThe established PBPK model of dronedarone was well validated with previously reported DDI studies. Reduced dosing regimens were recommended for patients administered apixaban and dronedarone together. For patients with renal impairment, both dosages of apixaban and rivaroxaban should be adjusted to avoid overexposure when dronedarone is co-administered.

Objective: By assessing the normal dimensions and the relationship between the aortic root and leaflets in Chinese population, the objective of this three-dimensional computed tomography (3DCT)-based study was to establish a matching reference for leaflets and aortic root for aortic valve (AV) repair.Method: Electrocardiogram-gated multi-detector CT was performed on 168 Chinese participants with a normal aortic valve. Measurements of the aortic annuli and leaflets were obtained. The correlations between and the ratios of the specific root and leaflet measurements were analyzed. The references for the leaflet and root dimensions were suggested based on geometric height (gH) using a linear regression equation. The utility of the ratios was tested with CT images of 15 patients who underwent aortic valve repair.Result: The mean annulus diameter (AD), sino-tubular junction (STJ) diameter, geometric height (gH), effective height (eH), free margin length (FML), commissural height (ComH), inter-commissural distance (ICD), and coaptation height (CH) were 22.4 ± 1.7 mm, 27.3 ± 2, 0.4 mm, 15.5 ± 1.7 mm, 8.9 ± 1.2 mm, 32.0 ± 3.4 mm, 17.9 ± 1.9 mm, 23.1 ± 2.3 mm, and 3.1 ± 0.6 mm, respectively. The gH/AD, FML/ICD, and eH/ComH ratios were 0.69 ± 0.07, 1.38 ± 0.08, and 0.50 ± 0.07, respectively. The gH correlated with all other leaflet and root measurements (P < 0.01), whereas the FML demonstrated a better correlation with ICD compared with gH (R2 = 0.75, and R2 = 0.37, respectively). The FML/ICD and eH/ComH ratios might be used to assess leaflet-root mismatch and post-repair leaflet billowing.Conclusion: The normal aortic valve measurements based on 3DCT revealed a specific relationship between the root and leaflets; and this will guide the development of an objective method of aortic valve repair.

ObjectivesConcern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA.MethodsWe performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2

Author(s): Lane, Jennifer CE; Weaver, James; Kostka, Kristin; Duarte-Salles, Talita; Abrahao, Maria Tereza F; Alghoul, Heba; Alser, Osaid; Alshammari, Thamir M; Areia, Carlos; Biedermann, Patricia; Banda, Juan M; Burn, Edward; Casajust, Paula; Fister, Kristina; Hardin, Jill; Hester, Laura; Hripcsak, George; Kaas-Hansen, Benjamin Skov; Khosla, Sajan; Kolovos, Spyros; Lynch, Kristine E; Makadia, Rupa; Mehta, Paras P; Morales, Daniel R; Morgan-Stewart, Henry; Mosseveld, Mees; Newby, Danielle; Nyberg, Fredrik; Ostropolets, Anna; Woong Park, Rae; Prats-Uribe, Albert; Rao, Gowtham A; Reich, Christian; Rijnbeek, Peter; Sena, Anthony G; Shoaibi, Azza; Spotnitz, Matthew; Subbian, Vignesh; Suchard, Marc A; Vizcaya, David; Wen, Haini; Wilde, Marcel de; Xie, Junqing; You, Seng Chan; Zhang, Lin; Lovestone, Simon; Ryan, Patrick; Prieto-Alhambra, Daniel; OHDSI-COVID-19 consortium | Abstract: ObjectivesConcern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA.MethodsWe performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 l40%.ResultsA total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis.ConclusionHCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation.Trial registrationRegistered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.

Background Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. Methods In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I² value was less than 0·4. Findings The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Selfcontrolled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12–2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22–3·95]), chest pain or angina (1·15 [1·05–1·26]), and heart failure (1·22 [1·02–1·45]). Interpretation Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit–risk trade-off when counselling those on hydroxychloroquine treatment.

Background To better understand the profile of individuals with severe coronavirus disease 2019 (COVID-19), we characterised individuals hospitalised with COVID-19 and compared them to individuals previously hospitalised with influenza. Methods We report the characteristics (demographics, prior conditions and medication use) of patients hospitalised with COVID-19 between December 2019 and April 2020 in the US (Columbia University Irving Medical Center [CUIMC], STAnford Medicine Research data Repository [STARR-OMOP], and the Department of Veterans Affairs [VA OMOP]) and Health Insurance Review & Assessment [HIRA] of South Korea. Patients hospitalised with COVID-19 were compared with patients previously hospitalised with influenza in 2014–19. Results 6,806 (US: 1,634, South Korea: 5,172) individuals hospitalised with COVID-19 were included. Patients in the US were majority male (VA OMOP: 94%, STARR-OMOP: 57%, CUIMC: 52%), but were majority female in HIRA (56%). Age profiles varied across data sources. Prevalence of asthma ranged from 7% to 14%, diabetes from 18% to 43%, and hypertensive disorder from 22% to 70% across data sources, while between 9% and 39% were taking drugs acting on the renin-angiotensin system in the 30 days prior to their hospitalisation. Compared to 52,422 individuals hospitalised with influenza, patients admitted with COVID-19 were more likely male, younger, and, in the US, had fewer comorbidities and lower medication use. Conclusions Rates of comorbidities and medication use are high among individuals hospitalised with COVID-19. However, COVID-19 patients are more likely to be male and appear to be younger and, in the US, generally healthier than those typically admitted with influenza.

ObjectivesConcern has been raised in the rheumatological community regarding recent regulatory warnings that hydroxychloroquine used in the COVID-19 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation, or psychosis associated with hydroxychloroquine as used for rheumatoid arthritis (RA).MethodsNew user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and US). RA patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine (active comparator) and followed up in the short (30-day) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation, and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HR), with estimates pooled where I2Results918,144 and 290,383 users of hydroxychloroquine and sulfasalazine, respectively, were included. No consistent risk of psychiatric events was observed with short-term hydroxychloroquine (compared to sulfasalazine) use, with meta-analytic HRs of 0.96 [0.79-1.16] for depression, 0.94 [0.49-1.77] for suicide/suicidal ideation, and 1.03 [0.66-1.60] for psychosis. No consistent long-term risk was seen, with meta-analytic HRs 0.94 [0.71-1.26] for depression, 0.77 [0.56-1.07] for suicide/suicidal ideation, and 0.99 [0.72-1.35] for psychosis.ConclusionsHydroxychloroquine as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation, or psychosis compared to sulfasalazine. No effects were seen in the short or long term. Use at higher dose or for different indications needs further investigation.TRIAL REGISTRATIONRegistered with EU PAS; Reference number EUPAS34497 (http://www.encepp.eu/encepp/viewResource.htm?id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine.WHAT IS ALREADY KNOWN ON THIS TOPICRecent regulatory warnings have raised concerns of potential psychiatric side effects of hydroxychloroquine at the doses used to treat COVID-19, generating concern in the rheumatological communitySerious psychiatric adverse events such as suicide, acute psychosis, and depressive episodes have been identified by the US Food and Drug Administration (FDA) adverse events reporting system and at case report levelWHAT THIS STUDY ADDSThis is the largest study on the neuro-psychiatric safety of hydroxychloroquine to date, including >900,000 users treated for their RA in country-level or private health care systems in Germany, the UK, and the USWe find no association between the use of hydroxychloroquine and the risk of depression, suicide/suicidal ideation, or severe psychosis compared to sulfasalazineHOW MIGHT THIS IMPACT ON CLINICAL PRACTICEOur data shows no association between hydroxychloroquine treatment for RA and risk of depression, suicide or psychosis compared to sulfasalazine. These findings do not support stopping or switching hydroxychloroquine treatment as used for RA due to recent concerns based on COVID-19 treated patients.

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19., Detailed knowledge of the characteristics of COVID-19 patients helps with public health planning. Here, the authors use routinely-collected data from seven databases in three countries to describe the characteristics of >30,000 patients admitted with COVID-19 and compare them with those admitted for influenza in previous years.

Preclinical studies have shown that anti-cytokine therapies could alter drug dispositions through affecting cytochrome P450 synthesis; however, evidence and case reports evaluating clinical relevance of this interaction are scarce. This is the first reported case of interaction between cyclosporine (CsA) and etanercept in a 42-year-old male patient with ankylosing spondylitis and immunoglobulin A nephropathy in whom cytokine levels were monitored both before and after CsA initiation. The initiation of etanercept led to at least 2.5-folds increase in total clearance of CsA. After comprehensive assessment and stepwise exclusion of alternative causes, it was considered that inflammation resolution with etanercept administration has highly induced clearance of CsA, probably mediated by interleukin-2. The case has shown that co-administration of CsA and anti-cytokine therapies such as etanercept needs close monitoring of trough levels. Physicians and pharmacists should be aware of similar interactions especially when the biological therapy is initiated or discontinued and for patients undergoing acute inflammation phase. Monitoring cytokine levels should be considered when drug-cytokine interaction is suspected.

BackgroundHydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin.MethodsNew user cohort studies were conducted including 16 severe adverse events (SAEs). Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days. Self-controlled case series (SCCS) were conducted to further establish safety in wider populations. Separately, SAEs associated with hydroxychloroquine- azithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UK, and USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (CalHRs) according to drug use. Estimates were pooled where I2ResultsOverall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included. No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22- 3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02- 1.45])ConclusionsShort-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19.Trial registration numberRegistered with EU PAS; Reference number EUPAS34497 (http://www.encepp.eu/encepp/viewResource.htm?id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine.Funding sourcesThis research received partial support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and Senior Research Fellowship (DPA), US National Institutes of Health, Janssen Research & Development, IQVIA, and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI16C0992]. Personal funding included Versus Arthritis [21605] (JL), MRC-DTP [MR/K501256/1] (JL), MRC and FAME (APU). The European Health Data & Evidence Network has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. No funders had a direct role in this study. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Clinician Scientist Award programme, NIHR, NHS or the Department of Health, England.

Background Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. Methods In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I2 value was less than 0·4. Findings The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12–2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22–3·95]), chest pain or angina (1·15 [1·05–1·26]), and heart failure (1·22 [1·02–1·45]). Interpretation Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit–risk trade-off when counselling those on hydroxychloroquine treatment. Funding National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.

Supplemental material, OPP880604 Supplemetal Material for A simple method to identify undiagnosed drug-induced liver injury (DILI) and its application in oncology pharmacy practice by Haini Wen, Maojun Ge, Di Yao and Li Liu in Journal of Oncology Pharmacy Practice