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Adverse Events Associated With Radium-223 in Metastatic Prostate Cancer: Disproportionality Analysis of FDA Data Reflecting Worldwide Utilization

Published:December 04, 2019DOI:https://doi.org/10.1016/j.clgc.2019.11.017

      Abstract

      Background

      Radionuclide radium-223 improves survival in men with metastatic castrate-resistant prostate cancer. The United States (US) Food and Drug Administration Adverse Events Reporting System (FAERS) is a post-market pharmacovigilance database valuable for adverse event (AE) assessments. We analyzed FAERS to identify disproportionate AE signals related to radium-223, and to explore radium-223’s international utilization.

      Materials and Methods

      We identified 2182 radium-223 cases associated with AE(s) from 2013 to 2018. The duration of radium-223 therapy was calculated. Reporting odds ratio (ROR) and proportional reporting ratio (PRR), with 95% confidence intervals (CIs), were calculated for AEs of interest. ROR shows disproportionate signals if the lower limit of the 95% CI > 1. PRR shows disproportionate signals if PRR ≥ 2, χ2 statistic ≥ 4, and ≥ 3 AEs were reported. We identified any US Food and Drug Administration enforcement actions for radium-223.

      Results

      A majority (60.8%) of events occurred outside the US. Among patients with radium-223-associated AEs, the median therapy duration was only 56 days (corresponding to 2-3 treatment cycles). Disproportionate signals were detected for general health deterioration (ROR, 5.03; 95% CI, 4.23-5.98 and PRR, 4.94; 95% CI, 4.16-5.87), bone pain (ROR, 4.53; 95% CI, 3.67-5.59 and PRR, 4.48; 95% CI, 3.63-5.53), and hematologic AEs including anemia (ROR, 2.89; 95% CI, 2.55-3.27 and PRR, 2.80; 95% CI, 2.48-3.17), thrombocytopenia (ROR, 3.22; 95% CI, 2.77-3.74 and PRR, 3.16; 95% CI, 2.72-3.67), and pancytopenia/bone marrow failure (ROR, 4.83; 95% CI, 4.11-5.67 and PRR, 4.73; 95% CI, 4.03-5.55). There were no enforcement actions for radium-223.

      Conclusions

      Patients with metastatic castrate-resistant prostate cancer experiencing AEs are only receiving one-half the prescription dose of radium-223 required for survival benefit. Radium-223 is associated with health deterioration, bone pain, and hematologic AEs. Real-world analyses are important for ongoing radium-223 risk-benefit assessments.

      Keywords

      Introduction

      In 2013, the ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial revealed improved overall survival in men with metastatic castrate-resistant prostate cancer (mCRPC) and bone metastases treated with alpha-emitter radium-223.
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • et al.
      ALSYMPCA Investigators
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      These results led to radium-223 being recommended (with a flash update on July 9, 2013) as a category 1 treatment option per the National Comprehensive Cancer Network guidelines for men with mCPRC and symptomatic bone metastases.
      ,
      NCCN Guidelines Updated: NCCN Flash Update sent July 9, 2013.
      Radium-223 has an 11.4-day half-life, is given to patients intravenously monthly for 6 total injections,
      United States Food and Drug Administration
      Xofigo® (Radium Ra 223 Dichloride) Injection, 1000 KBq/ML (0.027 Microcurie/ML); 2013.
      and is selectively taken up by bone with high osteoblastic activity by acting as a calcium analog.
      • Deshayes E.
      • Roumiguie M.
      • Thibault C.
      • et al.
      Radium 223 dichloride for prostate cancer treatment.
      Radium-223 is mainly excreted from the body via the gastrointestinal tract.
      • Deshayes E.
      • Roumiguie M.
      • Thibault C.
      • et al.
      Radium 223 dichloride for prostate cancer treatment.
      As of 2017, an estimated > 27,000 men have received radium-223 worldwide.
      • Deshayes E.
      • Roumiguie M.
      • Thibault C.
      • et al.
      Radium 223 dichloride for prostate cancer treatment.
      The United States (US) Food and Drug Administration (FDA) has a publicly available Adverse Events Reporting System (FAERS), which is critical for post-market surveillance of drugs approved for use in the US.
      United States Food and Drug Administration
      Questions and Answers on FDA’s Adverse Event Reporting System (FAERS).
      • Wysowski D.K.
      • Swartz L.
      Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: the importance of reporting suspected reactions.
      • Rodriguez E.M.
      • Staffa J.A.
      • Graham D.J.
      The role of databases in drug postmarketing surveillance.
      Toxicity and safety data from drug randomized clinical trials (RCTs), which are meticulously run with strict patient enrollment criteria, can be underreported
      • Seruga B.
      • Sterling L.
      • Wang L.
      • Tannock I.F.
      Reporting of serious adverse drug reactions of targeted anticancer agents in pivotal phase III clinical trials.
      ,
      • Sivendran S.
      • Latif A.
      • McBride R.B.
      • et al.
      Adverse event reporting in cancer clinical trial publications.
      and may conflict with real-world adverse events (AEs). FAERS studies can identify AEs not previously recognized in RCTs,
      United States Food and Drug Administration
      Questions and Answers on FDA’s Adverse Event Reporting System (FAERS).
      • Wysowski D.K.
      • Swartz L.
      Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: the importance of reporting suspected reactions.
      • Rodriguez E.M.
      • Staffa J.A.
      • Graham D.J.
      The role of databases in drug postmarketing surveillance.
      suggesting there is considerable value in analyzing these data. Rather than just reporting the incidence rates of AEs,
      • Brinker A.
      • Cheng C.
      • Chan V.
      Association of noninfectious pneumonia with ustekinumab use.
      disproportionality analyses are valuable for detecting AEs by searching for signals relative to other AEs reported to the FDA. Disproportionate AEs signals for multiple cancer drugs, including immunotherapies, chemotherapies, and targeted therapies, have been identified via FAERS.
      • Shamloo B.K.
      • Chhabra P.
      • Freedman A.N.
      • Potosky A.
      • Malin J.
      • Weiss Smith S.
      Novel adverse events of bevacizumab in the US FDA adverse event reporting system database: a disproportionality analysis.
      • Sanagawa A.
      • Hotta Y.
      • Kataoka T.
      • et al.
      Hepatitis B infection reported with cancer chemotherapy: analyzing the US FDA Adverse Event Reporting System.
      • Ali A.K.
      • Watson D.E.
      Pharmacovigilance assessment of immune-mediated reactions reported for checkpoint inhibitor cancer immunotherapies.
      • Soldatos T.G.
      • Dimitrakopoulou-Strauss A.
      • Larribere L.
      • Hassel J.C.
      • Sachpekidis C.
      Retrospective side effect profiling of the metastatic melanoma combination therapy ipilimumab-nivolumab using adverse event data.
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      • Sakhiya V.
      • Fishbane S.
      Nephrotoxicity of the BRAF inhibitors vemurafenib and dabrafenib.
      • Oshima Y.
      • Tanimoto T.
      • Yuji K.
      • Tojo A.
      EGFR–TKI-associated interstitial pneumonitis in nivolumab-treated patients with non–small cell lung cancer.
      • Wittayanukorn S.
      • Qian J.
      • Johnson B.S.
      • Hansen R.A.
      Cardiotoxicity in targeted therapy for breast cancer: a study of the FDA adverse event reporting system (FAERS).
      Prior work evaluating radiotherapy AEs reported to the FDA has focused primarily on medical devices (computed tomography simulators, external beam devices, brachytherapy systems, etc) and software systems
      • Connor M.J.
      • Marshall D.C.
      • Moiseenko V.
      • et al.
      Adverse events involving radiation oncology medical devices: comprehensive analysis of US Food and Drug Administration data, 1991 to 2015.
      and the associated FDA-mandated recalls of these devices.
      • Connor M.J.
      • Tringale K.
      • Moiseenko V.
      • et al.
      Medical device recalls in radiation oncology: analysis of US Food and Drug Administration data, 2002-2015.
      Little is known about reported AEs regarding radionuclides.
      Given FAERS’ uniqueness as a real-world risk assessment tool, we performed a comprehensive disproportionality analysis to determine AE signals related to radium-223 use. Furthermore, we explored radium-223’s real-world utilization: who is receiving this radionuclide, and for what indication? Are patients receiving the entire 6-injection course, and what is the relationship of AE onset with therapy duration? Finally, what are the trends of radium-223 use and reported AEs over time?

      Materials and Methods

       Data Source

      FAERS is a live, spontaneous reporting system containing AE or medication error reports submitted to the FDA from sources including pharmaceutical companies, physicians, lawyers, consumers, and the general public.
      United States Food and Drug Administration
      Questions and Answers on FDA’s Adverse Event Reporting System (FAERS).
      Direct reports are voluntarily sent by consumers and medical professionals. Mandatory reports are submitted by drug manufacturers and are “expedited” 15-day reports (containing at least 1 AE not currently in the product labeling and for which the outcome is serious) or “periodic” reports (these reports do not meet criteria for an expedited report and must be submitted quarterly for the first 3 years after approval, and annually after).
      United States Food and Drug Administration
      FDA Adverse Events Reporting System (FAERS) - Reports received and reports entered into FAERS by year.
      One report may contain multiple drugs, indications, or AEs.
      FAERS is a relational database. Data is aggregated into quarterly extract files. There are 7 files in each release: “DEMO” containing demographics about the patient who experienced the event (age, gender, country) and the reporter occupation; “DRUG” with drug information and its suspected role in the reported AE; “INDI” with the drug use indication; “RPSR” detailing the report source; “THER” containing the start and end dates of the therapy; “REAC” containing the AE(s); and “OUTC” revealing the outcome and severity. All files are linked by a unique primary ID consisting of the case ID and the revision number. Each case represents 1 patient and is linked to all drugs administered to that individual. Because patient outcomes are listed on a per-patient basis (not a per-drug basis), we limited the cases to those where radium-223 was the primary or secondary suspect drug.
      Because the FDA approved radium-223 use on May 15, 2013,
      United States Food and Drug Administration
      Xofigo® (Radium Ra 223 Dichloride) Injection, 1000 KBq/ML (0.027 Microcurie/ML); 2013.
      we queried FAERS from 2013 quarter 2 (2013Q2) through 2018 quarter 2 (2018Q2). Quarterly data files were downloaded on September 6, 2018. Duplicate reports were removed as per FDA guidelines of adopting the most recent case number for disproportionality analyses.
      • Sakaeda T.
      • Tamon A.
      • Kadoyama K.
      • Okuno Y.
      Data mining of the public version of the FDA adverse event reporting system.
      Analyses were performed in Python 3.6.

       Radium-223 AEs and Outcomes

      We searched for all reports in the “DRUG” files where the drug name contained one of the following terms: “radium” or the brand name “Xofigo.” Case IDs were subsequently used to search for AEs of interest related to radium-223 as composite groups. These AEs were chosen a priori from radium-223’s mechanisms of action
      • Deshayes E.
      • Roumiguie M.
      • Thibault C.
      • et al.
      Radium 223 dichloride for prostate cancer treatment.
      and clinical trials,
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • et al.
      ALSYMPCA Investigators
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      ,
      • Parker C.
      • Heidenreich A.
      • Nilsson S.
      • Shore N.
      Current approaches to incorporation of radium-223 in clinical practice.
      ,
      • Saad F.
      • Carles J.
      • Gillessen S.
      • et al.
      Radium-223 International Early Access Program Investigators
      Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.
      and are classified using the Medical Dictionary for Regulatory Activities Preferred Term nomenclature. AEs of interest were general health deterioration, fatigue, decreased appetite, dehydration, vomiting, diarrhea, nausea, bone pain, anemia, thrombocytopenia, leukopenia, neutropenia, pancytopenia/bone marrow failure, peripheral edema, pulmonary toxicity, and renal toxicity. Full search terms are detailed in Supplemental Table 1 (in the online version). A patient could be binned into multiple AE composite groups but could only be placed into each group once.
      We categorized the following FAERS pre-specified patient outcomes in mutually exclusive outcome groups in order of seriousness: death, life-threatening, hospitalization, disability, required intervention, and “other serious/important medical event.”
      • Wittayanukorn S.
      • Qian J.
      • Johnson B.S.
      • Hansen R.A.
      Cardiotoxicity in targeted therapy for breast cancer: a study of the FDA adverse event reporting system (FAERS).
      The median and interquartile range (IQR) for radium-223 therapy duration, AE onset after radium-223 therapy initiation, AE persistence after radium-223 was stopped, and AE reporting time lag (time between AE occurrence and report submission) were calculated.

       Disproportionality Analysis

      A disproportionality analysis was then performed using established FAERS data mining methods.
      • Hesha J.
      • Duggirala C.J.
      • Joseph M.
      • et al.
      • Poluzzi E.
      • Raschi E.
      • Piccinni C.
      • De Ponti F.
      Data mining techniques in pharmacovigilance: analysis of the publicly accessible FDA Adverse Event Reporting System (AERS).
      • Bate A.
      • Evans S.J.W.
      Quantitative signal detection using spontaneous ADR reporting.
      A proportional reporting ratio (PRR) and reporting odds ratio (ROR), and their respective 95% confidence intervals (CIs), were calculated for each AE. The PRR represents the rate of reporting 1 event among all events for a given drug (eg, radium-223), compared with the reporting rate for all drugs in the database.
      • Poluzzi E.
      • Raschi E.
      • Piccinni C.
      • De Ponti F.
      Data mining techniques in pharmacovigilance: analysis of the publicly accessible FDA Adverse Event Reporting System (AERS).
      The ROR is the ratio of the odds of reporting 1 event versus all other events for a given drug, compared with the odds for all other drugs in FAERS.
      • Poluzzi E.
      • Raschi E.
      • Piccinni C.
      • De Ponti F.
      Data mining techniques in pharmacovigilance: analysis of the publicly accessible FDA Adverse Event Reporting System (AERS).
      The PRR, ROR, and their 95% CIs are calculated based on a 2-by-2 contingency table (Table 1) and are defined in Equations ((1), (2)).
      PRR=A/(A+B)C/(C+D);95%CI=eln(PRR)±1.961A+1B+1C+1D
      (1)


      ROR=A/CB/D;95%CI=eln(ROR)±1.961A+1B+1C+1D
      (2)


      Table 1Two-by-two Contingency Table Used for Calculation of the ROR and PRR
      Adverse Drug Event of InterestAll Other Drug Adverse EventsTotal
      Radium-223 (drug of interest)ABA + B
      All other drugs in FAERS databaseCDC + D
      TotalA + CB + DA + B + C + D
      Abbreviations: FAERS = United States Food and Drug Administration Adverse Events Reporting System; PRR = proportional reporting ratio; ROR = reporting odds ratio.
      The ROR is defined as A/CB/D;95%CI=eln(ROR)±1.961A+1B+1C+1D, whereas the PRR is defined A/(A+B)C/(C+D);95%CI=eln(PRR)±1.961A+1B+1C+1D.
      A PRR shows a disproportionate, or strong, signal for an AE if PRR ≥ 2, the χ2 statistic χ2 ≥ 4, and ≥ 3 events were reported.
      • Evans S.J.W.
      • Waller P.C.
      • Davis S.
      Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports.
      An ROR shows a disproportionate signal if the lower limit of the 95% CI > 1 and ≥ 2 events were reported.
      • Finney D.J.
      Systemic signalling of adverse reactions to drugs.

       Report Characteristics and Events Over Time

      To evaluate whether there was a statistically significant increase in cases reported over time, we performed linear regressions of the number of cases reported against time (in quarters). We additionally performed linear regressions of the number of outcomes (death, hospitalization, life-threatening, disability) and all AEs reported against time. Analyses were corrected for multiple comparisons to control the false discovery rate.
      • Benjamini Y.
      • Hochberg Y.
      Controlling the false discovery rate: a practical and powerful approach to multiple testing.
      Statistical significance was set at α = .05.

       Drug Enforcement and Recalls

      As a secondary analysis of radium-223 events, we searched the FDA Drug Recall Enforcement Reports
      US Food and Drug Administration
      Enforcement Reports.
      to identify any recalls or enforcement actions from 2013Q2 to 2018Q2.

      Results

      There were 6,356,962 patient cases involving AEs reported to FAERS from 2013Q2 to 2018Q2; of these, 5,898,241 were unique cases. There were 2182 unique patient cases involving radium-223 (see Supplemental Figure 1 in the online version).

       Patients and Report Characteristics

      Patient and report characteristics of all unique cases are shown in Table 2. Of the 1270 (58.2%) cases where age was reported, the mean age of patients receiving radium-223 was 71.6 years (standard deviation, 9.6 years). Over 90% (n = 1981) of reported cases were of male patients. Radium-223 indications included prostate cancer (n = 1429; 59.6%), metastases (n = 814; 35.1%), pain (n = 17; 0.7%), disease progression (n = 4; 0.1%), and palliative care (n = 2; 0.0%); 105 (4.4%) cases did not have a reported indication.
      Table 2Patient and Report Characteristics of the 2182 Unique Cases of Radium-223 Reported to FAERS, 2013Q2 to 2018Q2
      CharacteristicRadium-223 Reports, n = 2182 (%)
      Patient’s age, y
       Mean (SD)71.6 (9.6)
       <5022 (1.0)
       50-5984 (3.8)
       60-69417 (19.1)
       70-79467 (21.4)
       80-89261 (12.0)
       ≥9019 (0.9)
       Unknown/other912 (41.8)
      Gender
       Male1981 (90.8)
       Unknown/other201 (9.2)
      Continent of occurrence
      Countries were placed into geographic continents.
       North America
      North America: USA (n = 856), Canada (n = 37), Mexico (n = 7), Puerto Rico (n = 1).
      901 (41.3)
       Europe
      Europe: Switzerland (n = 133), Germany (n = 102), United Kingdom (n = 91), Netherlands (n = 67), Belgium (n = 63), Spain (n = 46), Ireland (n = 33), Finland (n = 25), France (n = 25), Austria (n = 21), Hungary (n = 15), Italy (n = 14), Sweden (n = 14), Slovakia (n = 12), Norway (n = 12), Portugal (n = 10), Bulgaria (n = 9), Denmark (n = 8), Slovenia (n = 8), Croatia (n = 4), Luxembourg (n = 4), Russia (n = 3), Lithuania (n = 2), Greece (n = 1), Poland (n = 1).
      844 (38.7)
       Asia
      Asia: Japan (n = 303), Israel (n = 122), Singapore (n = 23), China (n = 9), Hong Kong (n = 9), Taiwan (n = 5), South Korea (n = 2), Thailand (n = 2), India (n = 1).
      354 (16.2)
       South America
      South America: Brazil (n = 35), Colombia (n = 13), Argentina (n = 8).
      56 (2.6)
       Australia
      Australia: n = 11.
      11 (0.5)
       Africa
      Africa: South Africa (n = 4).
      4 (0.2)
       Unknown12 (0.5)
      Indication for radium-223 use
      Numbers add up to more than the number of cases as there may be more than one indication per case.
      N = 2398
       Prostate cancer
      “hormone-dependent prostate cancer,” “hormone-refractory prostate cancer,” “neoplasm prostate,” “prostate cancer,” “prostate cancer metastatic,” “prostate cancer stage IV,” “prostatic specific-antigen increased”.
      1429 (59.6)
       Metastases
      “metastases,” “metastatic pain,” “metastases to bone,” “metastases to bone marrow,” “metastases to spine”.
      841 (35.1)
       Pain
      “pain,” “bone pain,” “cancer pain,” “pain in extremity,” “pain management,” “back pain”.
      17 (0.7)
       Disease progression
      “disease progression”.
      4 (0.1)
       Palliative care
      “palliative care”.
      2 (0.0)
       Unknown/other105 (4.4)
      Reporter occupation
       Physician1167 (53.5)
       Consumer597 (27.4)
       Other health professional385 (17.6)
       Pharmacist28 (1.3)
       Unknown/other5 (0.2)
      Report type
       Expedited (15-day report from manufacturer)1850 (84.8)
       Periodic (non-expedited report from manufacturer)301 (13.8)
       Direct (voluntary reports submitted by non-manufacturers)31 (1.4)
      Report year
       201369 (3.2)
       2014277 (12.7)
       2015362 (16.6)
       2016391 (17.9)
       2017657 (30.1)
       2018426 (19.5)
      Abbreviations: FAERS = United States Food and Drug Administration Adverse Events Reporting System; Q = quarter; SD = standard deviation.
      a Countries were placed into geographic continents.
      b North America: USA (n = 856), Canada (n = 37), Mexico (n = 7), Puerto Rico (n = 1).
      c Europe: Switzerland (n = 133), Germany (n = 102), United Kingdom (n = 91), Netherlands (n = 67), Belgium (n = 63), Spain (n = 46), Ireland (n = 33), Finland (n = 25), France (n = 25), Austria (n = 21), Hungary (n = 15), Italy (n = 14), Sweden (n = 14), Slovakia (n = 12), Norway (n = 12), Portugal (n = 10), Bulgaria (n = 9), Denmark (n = 8), Slovenia (n = 8), Croatia (n = 4), Luxembourg (n = 4), Russia (n = 3), Lithuania (n = 2), Greece (n = 1), Poland (n = 1).
      d Asia: Japan (n = 303), Israel (n = 122), Singapore (n = 23), China (n = 9), Hong Kong (n = 9), Taiwan (n = 5), South Korea (n = 2), Thailand (n = 2), India (n = 1).
      e South America: Brazil (n = 35), Colombia (n = 13), Argentina (n = 8).
      f Australia: n = 11.
      g Africa: South Africa (n = 4).
      h Numbers add up to more than the number of cases as there may be more than one indication per case.
      i “hormone-dependent prostate cancer,” “hormone-refractory prostate cancer,” “neoplasm prostate,” “prostate cancer,” “prostate cancer metastatic,” “prostate cancer stage IV,” “prostatic specific-antigen increased”.
      j “metastases,” “metastatic pain,” “metastases to bone,” “metastases to bone marrow,” “metastases to spine”.
      k “pain,” “bone pain,” “cancer pain,” “pain in extremity,” “pain management,” “back pain”.
      l “disease progression”.
      m “palliative care”.
      Reported cases occurred in 43 countries, with the majority (60.8%) occurring outside the US. The 5 most common countries of occurrence were the US (n = 856; 39.2%), Japan (n = 303; 13.9%), Switzerland (n = 133; 6.1%), Israel (n = 122; 5.6%), and Germany (n = 102; 4.7%). Most cases occurred in North America (41.3%), Europe (38.7%), or Asia (16.2%).
      Regarding the reports, most were submitted by physicians (n = 1167; 53.5%), followed by consumers (n = 597; 27.4%) and other health professionals (n = 364; 17.6%). Most reports were expedited (n = 1850; 84.8%), 301 (13.8%) were periodic, and 31 (1.4%) were direct.

       Outcomes, AEs, and Disproportionality

      Characteristics of the events and outcomes are delineated in Table 3. The event outcomes were death in 425 (19.5%) cases, life-threatening in 42 (1.9%), hospitalization in 484 (22.2%), disability in 9 (0.4%), other serious outcome in 942 (43.2%); 280 (12.8%) had no reported outcome. Radium-223 was the primary suspect in the AE in 39.1% of cases. The median duration of radium-223 therapy was 56 days (IQR, 1-98 days). The median AE onset after radium-223 initiation was 48 days (IQR, 14-97 days), whereas the median AEs persistence after radium-223 was stopped was 16 days (IQR, 3-31 days). The median AE reporting time lag was 67 days (IQR, 25-157 days).
      Table 3Outcome of Events and Temporality Information for the 2182 Cases of Radium-223 Reported to FAERS
      CharacteristicRadium-223 Reports, n = 2182 (%)
      Outcome of serious event
       Death425 (19.5)
       Life-threatening42 (1.9)
       Hospitalization484 (22.2)
       Disability9 (0.4)
       Required intervention0 (0.0)
       Other serious/important medical event942 (43.2)
       Unknown280 (12.8)
      Radium-223 role in event
       Primary suspect855 (39.1)
       Secondary suspect1327 (60.8)
      Temporality in days (median and IQR), number of valid cases
       Duration of radium-223 therapy
      Time between date of radium-223 start and stop.
      56 (IQR, 1-98), n = 790
       Onset of AE after radium-223 started
      Time between date of radium-223 start and AE occurrence.
      48 (IQR, 14-97), n = 647
       Persistence of AE after radium-223 stopped
      Time between date of radium-223 stop and AE occurrence.
      16 (IQR, 3-31), n = 333
       AE reporting time lag
      Time between date of AE occurrence and report submission.
      67 (IQR, 25-157), n = 760
      Abbreviations: AE = adverse event; FAERS = United States Food and Drug Administration Adverse Events Reporting System; IQR = interquartile range.
      a Time between date of radium-223 start and stop.
      b Time between date of radium-223 start and AE occurrence.
      c Time between date of radium-223 stop and AE occurrence.
      d Time between date of AE occurrence and report submission.
      Table 4 shows the disproportionality results for radium-223 AEs. Disproportionate signals were detected for general health deterioration (ROR, 5.03; 95% CI, 4.23-5.98 and PRR, 4.94; 95% CI, 4.16-5.87) and bone pain (ROR, 4.53; 95% CI, 3.67-5.59 and PRR, 4.48; 95% CI, 3.63-5.53). Strong signals were detected for hematologic toxicities, including anemia (ROR, 2.89; 95% CI, 2.55-3.27 and PRR, 2.80; 95% CI, 2.48-3.17), thrombocytopenia (ROR, 3.22; 95% CI, 2.77-3.74 and PRR, 3.16; 95% CI, 2.72-3.67), and pancytopenia/bone marrow failure (ROR, 4.83; 95% CI, 4.11-5.67 and PRR, 4.73; 95% CI, 4.03-5.55). There was a strong leukopenia signal with the ROR (1.47; 95% CI, 1.16-1.86) but not the PRR (1.47; 95% CI, 1.16-1.86). No disproportionate ROR or PRR signals were detected for the other AEs.
      Table 4Disproportionality Analysis of Adverse Events for Radium-223, With the ROR and PRR, Their Respective 95% CIs, and the χ2 Value
      Adverse EventNumber of Events Reported for Radium-223ROR (95% CI)PRR (95% CI)χ2
      General health deterioration1335.03 (4.23-5.98)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      4.94 (4.16-5.87)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      413.45
      Fatigue1930.50 (0.43-0.58)0.52 (0.45-0.60)92.19
      Decreased appetite761.10 (0.88-1.38)1.09 (0.87-1.37)0.53
      Dehydration350.86 (0.62-1.20)0.86 (0.62-1.20)0.69
      Vomiting720.53 (0.42-0.67)0.53 (0.42-0.67)29.49
      Diarrhea1220.65 (0.54-0.78)0.65 (0.54-0.78)22.62
      Nausea1310.55 (0.46-0.65)0.56 (0.47-0.67)47.99
      Bone pain884.53 (3.67-5.59)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      4.48 (3.63-5.53)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      234.01
      Anemia2652.89 (2.55-3.27)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      2.80 (2.48-3.17)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      309.96
      Thrombocytopenia1773.22 (2.77-3.74)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      3.16 (2.72-3.67)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      260.23
      Leukopenia711.47 (1.16-1.86)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      1.47 (1.16-1.86)10.18
      Neutropenia601.11 (0.86-1.43)1.11 (0.86-1.43)0.58
      Pancytopenia or bone marrow failure1544.83 (4.11-5.67)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      4.73 (4.03-5.55)
      Indicates a statistically significant disproportionate signal based on the PRR or ROR.
      449.09
      Peripheral edema390.46 (0.34-0.63)0.46 (0.34-0.63)24.16
      Pulmonary toxicity800.30 (0.24-0.37)0.31 (0.25-0.39)124.69
      Renal toxicity600.42 (0.33-0.54)0.43 (0.33-0.55)46.50
      Abbreviations: CI = confidence interval; PRR = proportional reporting ratio; ROR = reporting odds ratio.
      a Indicates a statistically significant disproportionate signal based on the PRR or ROR.

       Time Trends

      Linear regression of total reported radium-223 cases by quarter showed a significant increase in the raw number of cases reported to FAERS over time (R2 = 0.86; P < .001) (Figure 1A). After correction for multiple comparisons, similar significant increases were seen for the raw number of outcomes of disability (R2 = 0.25; P = .02), hospitalization (R2 = 0.83; P < .001), and death (R2 = 0.82; P < .001), but not life-threatening (R2 = 0.13; P = .11). The proportions of outcomes reported per quarter remained relatively constant throughout the study period (Figure 1B).
      Figure thumbnail gr1
      Figure 1Radium-223 Outcomes Reported to FAERS, 2013Q2 to 2018Q2. There Was a Significant Increase in Raw Number of Cases Reported to FAERS Over Time (A); Similar Significant Increases Were Seen in the Raw Number of the Disability, Hospitalization, and Death Outcomes. The Slopes (β) Indicate Reports per Quarter. B, the Proportion of Each Outcome, by Quarter
      Abbreviations: FAERS = United States Food and Drug Administration Adverse Events Reporting System; NCCN = National Comprehensive Cancer Network; Q = quarter.
      Linear regressions of AEs against report quarter revealed that all AEs increased significantly over time, after correction for multiple comparisons (Table 5).
      Table 5Linear Regressions of Adverse Events of Interest by Quarter
      Adverse EventβR-squaredP Value
      General health deterioration0.760.57<.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Fatigue0.890.79<.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Decreased appetite0.780.61<.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Dehydration0.760.57<.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Vomiting0.470.22.03
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Diarrhea0.850.72<.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Nausea0.630.40.002
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Bone pain0.780.61<.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Anemia0.840.71<.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Thrombocytopenia0.810.65<.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Leukopenia0.580.34.006
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Neutropenia0.630.39.002
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Pancytopenia or bone marrow failure0.790.63<.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Peripheral edema0.560.32.008
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Pulmonary toxicity0.720.51<.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      Renal toxicity0.680.47.001
      Indicates a statistically significant P value after corrections for the false-discovery rate.
      The slopes (β) indicate reports per quarter.
      a Indicates a statistically significant P value after corrections for the false-discovery rate.

       Drug Enforcement and Recalls

      There have been no FDA enforcement actions or recalls for radium-223 to date.

      Discussion

      Radium-223 is a key drug that improves survival in the treatment of patients with mCRPC. We present the first pharmacovigilance study of alpha-emitter radium-223. FAERS offers an important tool in the post-market surveillance of drugs approved by the FDA, by allowing for early identification of AEs, which may have been previously unrecognized, in a real-world setting. We found AEs associated with radium-223 reported from 6 continents, with nearly 80% of reported cases occurring in North America and Europe. International radium-223 use was associated with disproportionate signals for general health deterioration, bone pain, and hematologic AEs. Furthermore, the median duration of radium-223 use was less than one-half the number of cycles expected for maximum survival benefit. Although RCTs remain the gold standard for answering drug safety and efficacy questions, they may underreport AEs
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      and are run under controlled environments with highly selected patients. FAERS offers powerful population-level, international insight into spontaneous reporting of radium-223 toxicity, including duration of use and temporal changes over time, and into the actual patients who are receiving this radionuclide.
      Patients receiving radium-223 identified through FAERS were treated mainly for metastatic prostate cancer and were older (mean age, 71.6 years), reflecting the patient population eligible for radium-223.
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • et al.
      ALSYMPCA Investigators
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      ,
      • Parker C.
      • Heidenreich A.
      • Nilsson S.
      • Shore N.
      Current approaches to incorporation of radium-223 in clinical practice.
      ,
      • Saad F.
      • Carles J.
      • Gillessen S.
      • et al.
      Radium-223 International Early Access Program Investigators
      Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.
      The median duration of radium-223 use was only 56 days, corresponding to 2 to 3 monthly injections. This suggests some patients did not complete an entire radium-223 course; plausible reasons include toxicities, the development of visceral metastases, disease progression, or health deterioriation.
      • Parker C.
      • Heidenreich A.
      • Nilsson S.
      • Shore N.
      Current approaches to incorporation of radium-223 in clinical practice.
      All 6 cycles of radium-223 should be given for maximum survival benefit
      • Saad F.
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      Disease characteristics and completion of treatment in patients with metastatic castration-resistant prostate cancer treated with radium-223 in an international early access program.
      (the treatment arm in the ALSYMPCA trial received a median of 6 injections),
      • Parker C.
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      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      so if therapy was halted owing to dose-limiting toxicities, these AEs need thorough evaluation. Additionally, the median AE onset after radium-223 initiation was 46 days, but once an AE occurred and radium-223 was stopped, the AE persistence was relatively short (median, 16 days). Radium-223 toxicities, therefore, appear to dissipate rapidly after treatment is stopped, suggesting that therapy could be reinitiated in certain patients who experienced serious AEs.
      Our disproportionality analysis, conducted in a heterogenous and large group of patients, revealed strong PRR and ROR signals detected for multiple hematologic AEs (anemia, thrombocytopenia, pancytopenia/bone marrow failure, and leukopenia): these are concordant with known radium-223 AEs. Common toxicities in the ALSYMPCA trial were nausea, bone pain, and anemia.
      • Parker C.
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      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      Similar toxicities were seen in a separate study evaluating radium-223 with concomitant abiraterone and enzalutamide, where AEs included anemia, thrombocytopenia, fatigue, and bone pain.
      • Saad F.
      • Carles J.
      • Gillessen S.
      • et al.
      Radium-223 International Early Access Program Investigators
      Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.
      As FAERS represent real-world usage of radium-223, disproportionate AE signals are even more meaningful (as these are the AEs being observed by real-world radium-223 users) and can help clinicians in their counseling of patients receiving this radionuclide.
      Interestingly, leukopenia had disproportionate ROR, but not PRR, signals for radium-223. This is likely because the ROR and PRR infer disproportionality differently.
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      The PRR determines disproportionate AE reporting for a specific drug compared with the same AE for all other drugs reported to FAERS; it cannot estimate relative risk.
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      Conversely, the ROR interprets FAERS as a case-control study (where the cases are reports of an AE and controls are reports of all other AEs), thus providing a measure of relative risk.
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      The reporting odds ratio and its advantages over the proportional reporting ratio.
      This comparison of odds ratios can be unduly influenced by AE underreporting; the PRR is not similarly affected. Both PRRs and RORs, however, demonstrate stronger disproportionality with higher values.
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      ,
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      The reporting odds ratio and its advantages over the proportional reporting ratio.
      Our most disproportionate signals were detected for general health deterioration, bone pain, and pancytopenia/bone marrow failure. CIs are also needed to identify ROR signals and reduce false positives. When the observed and expected counts are both low, the CIs are wider, leading to decreased reliability.
      • Bate A.
      • Evans S.J.W.
      Quantitative signal detection using spontaneous ADR reporting.
      Notably, we did not find signals for diarrhea or nausea, a slightly discordant finding given radium-223’s gastrointestinal excretion and previously reported toxicity profile.
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • et al.
      ALSYMPCA Investigators
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      ,
      • Parker C.
      • Heidenreich A.
      • Nilsson S.
      • Shore N.
      Current approaches to incorporation of radium-223 in clinical practice.
      ,
      • Saad F.
      • Carles J.
      • Gillessen S.
      • et al.
      Radium-223 International Early Access Program Investigators
      Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.
      This may be because gastrointestinal AEs are fairly common. If a toxicity is frequently reported for all drugs in FAERS, the observed/expected values used in the PRR and ROR calculations are too similarly proportional. Disproportionality requires that an AE is reported more (or less) frequently for a specific drug. Lack of disproportionality from FAERS does not imply no gastrointestinal toxicity with radium-223 use. Rather, the only conclusion is that there was no disproportion seen for these gastrointestinal AEs.
      The most common named outcomes associated with radium-223 use were death (19.5%) and hospitalization (22.2%). Although this death rate appears high, 35% of patients receiving radium-223 on the ALSYMPCA trial died, and the median survival was only 14.9 months.
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • et al.
      ALSYMPCA Investigators
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      FAERS does not provide cause of death information, but these older patients may be dying of their mCRPC or from unrelated causes. Potentially some patients were hospitalized or died owing to other comorbidities/medications: radium-223 was the primary suspect drug in less than one-half of reported cases. The delineation of a drug as the primary/secondary suspect in an AE is designated by the reporter, but is subject to user interpretation of the AE in the context of the patient’s other medications at the time of the event. This may lead to under-reporting of radium-223 as the primary suspect. Most radium-223 reports were physician- (53.5%) or manufacturer-reported (> 98%); this is consistent with other FAERS reports evaluating cancer-directed therapies,
      • Shamloo B.K.
      • Chhabra P.
      • Freedman A.N.
      • Potosky A.
      • Malin J.
      • Weiss Smith S.
      Novel adverse events of bevacizumab in the US FDA adverse event reporting system database: a disproportionality analysis.
      ,
      • Ali A.K.
      • Watson D.E.
      Pharmacovigilance assessment of immune-mediated reactions reported for checkpoint inhibitor cancer immunotherapies.
      ,
      • Wittayanukorn S.
      • Qian J.
      • Johnson B.S.
      • Hansen R.A.
      Cardiotoxicity in targeted therapy for breast cancer: a study of the FDA adverse event reporting system (FAERS).
      and with AEs for radiation oncology devices reported to the FDA.
      • Connor M.J.
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      Adverse events involving radiation oncology medical devices: comprehensive analysis of US Food and Drug Administration data, 1991 to 2015.
      The high percentage of manufacturer reports may be because manufacturers are required to notify the FDA when a physician informs a drug manufacturer of AE(s). Perhaps these data altogether reflect the real-world usage of radium-223 where patients are not receiving radium-223 as monotherapy for their mCRPC, but are receiving it concomitantly with other therapies (ie, enzalutamide or abiraterone)
      • Saad F.
      • Carles J.
      • Gillessen S.
      • et al.
      Radium-223 International Early Access Program Investigators
      Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.
      or as in ongoing RCTs evaluating the efficacy of radium-223 combined with hormonal therapies, chemotherapy, or external beam radiotherapy.
      • Deshayes E.
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      • et al.
      Radium 223 dichloride for prostate cancer treatment.
      Our time-series data revealed an increase in the total cases of radium-223 reported to FAERS, and for each AE. These findings are consistent with expanded radium-223 research
      • Saad F.
      • Carles J.
      • Gillessen S.
      • et al.
      Radium-223 International Early Access Program Investigators
      Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.
      and increased use.
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      Successfully integrating radium Ra 223 dichloride injection into a urology practice.
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      Radium Ra 223 dichloride therapy in the private practice environment.
      Additionally, reporting patterns to the FDA can change over time, influenced by external factors including media marketing after approval.
      • Bate A.
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      Quantitative signal detection using spontaneous ADR reporting.
      The Weber effect describes rapid increases in AE reporting, usually in the first 2 years after a drug’s FDA approval; these reporting rates eventually level out and decrease.
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      This effect has been partially attributed to advertisement efforts and increased attention by physicians to novel therapies
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      Data mining techniques in pharmacovigilance: analysis of the publicly accessible FDA Adverse Event Reporting System (AERS).
      and can be further affected if a drug has recalls or regulatory actions placed against it.
      • Motola D.
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      • Leone R.
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      Influence of regulatory measures on the rate of spontaneous adverse drug reaction reporting in Italy.
      Although there was no Weber effect in radium-223 reports to FAERS over the 5 years spanned by this study, a future plateau may be forthcoming. Therapies newly approved by the FDA generally have lag-time before widespread adoption.
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      Barriers unique to radionuclide use include reimbursement issues,
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      Radium 223 dichloride for prostate cancer treatment.
      prescribing licensing requirements, and specialized clinic infrastructure.
      • Seeber J.C.
      Radium Ra 223 dichloride therapy in the private practice environment.
      These requirements may have contributed to slower radium-223 uptake, causing persistently increasing radium-223 AEs reports to the FDA over time.
      Limitations to our work include the inability to infer direct causality, which is inherent to the FAERS dataset. However, FAERS is well-validated for toxicity evaluations across many cancer and non-cancer drugs.
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      Also, reporting is mandatory for manufacturers, but voluntary for physicians and patients; thus, the extent of AEs in our study may be underreported.
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      Despite this, we found signals for general health deterioration, bone pain, and hematologic AEs. Reporting bias may also exist, such that more serious AEs are reported. Also, the FAERS dataset may be subject to variability in data completeness.
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      Additionally, we cannot infer the true incidence/prevalence of radium-223 AEs. Despite this, we performed disproportionality analyses, which are pharmacovigilance techniques designed for this very reason.
      United States Food and Drug Administration
      FDA Adverse Events Reporting System (FAERS) - Reports received and reports entered into FAERS by year.
      ,
      • Hesha J.
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      • et al.
      ,
      • Rothman K.J.
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      The reporting odds ratio and its advantages over the proportional reporting ratio.
      FAERS is the only dataset with which questions regarding worldwide drug utilization and toxicities can be examined. Despite these limitations, this is the first robust analysis of AEs associated with radium-223 use in the real-world and provides important insight into how patients actually receive radium-223.

      Conclusions

      International patients experiencing AEs reported to FAERS are only receiving one-half the prescription dose of radium-223—a finding highly relevant to clinical practice. Post-market, population-based radium-223 signal detection suggests associations with general health deterioration, bone pain, and hematologic AEs, highlighting the possible toxicity issues associated with radium-223. As there were increases in radium-223 cases reported to FAERS and in each AE over time, and radium-223 use does not appear to have reason to abate in the future, clinicians must continue careful counseling, observation, and monitoring of patients receiving radium-223. Overall, the benefit-to-risk ratio for radium-223 appears favorable, given the known survival advantage it affords men with mCRPC and bone metastases and the reasonable safety profile shown in this real-world analysis. Clinicians should reconsider early termination of radium-223 treatment as the 6-injection course is needed to maximize survival. Further investigation into how to mitigate and/or prevent radium-223 AEs is needed to increase the number of men able to complete therapy, but in the meantime, physicians should maximally optimize patients to receive a full radium-223 prescription.

       Clinical Practice Points

      • Radium-223 is an alpha-emitting radionuclide shown to improve overall survival in men with mCRPC and painful osseous metastases. It is given to patients intravenously for 6 total injections for maximal survival advantage. The FDA has a publicly available FAERS, which is critical for post-market surveillance of drugs approved for use in the US.
      • We performed a comprehensive disproportionality analysis to determine AE signals related to radium-223 use, and we explored the real-world use of radium-223 to determine who is receiving this medication (and why), and to identify trends of radium-223 use over time.
      • We found that that patients with mCRPC experiencing AEs are only receiving one-half the prescription dose of radium-223 required for survival benefit.
      • Radium-223 is associated with general health deterioration, bone pain, and hematologic AEs. Linear regression of total reported radium-223 cases by quarter showed a significant increase in cases reported to FAERS over time. There have been no FDA enforcement actions or recalls for radium-223 to date.
      • Real-world analyses using FAERS are important for ongoing risk-benefit assessment of radium-223 use in a population-based, longitudinal setting, with implications for clinical practice and patient counseling.

      Disclosure

      Dr Hattangadi-Gluth reports research funding from Varian Medical Systems , unrelated to the present study. The remaining authors have stated that they have no conflicts of interest.

      Acknowledgments

      This work was supported in part by National Institutes of Health (NIH) grant #1KL2TR001444 (JAH-G) and R01CA238783-01 (JAH-G). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

      Supplemental Data

      Supplemental Table 1Adverse Event Queries
      Adverse Event of InterestMedDRA PT
      General health deteriorationGeneral physical health deterioration
      FatigueMalaise
      Fatigue
      Decreased appetiteDecreased appetite
      DehydrationDehydration
      VomitingVomiting
      DiarrheaDiarrhoea
      NauseaNausea
      Bone painBone pain
      AnemiaAnaemia
      Haemoglobin decreased
      Haematocrit decreased
      Red blood cell count decreased
      Red blood cell count
      Erythropenia
      Haemoglobin abnormal
      ThrombocytopeniaThrombocytopenia
      Platelet count decreased
      LeukopeniaWhite blood cell count decreased
      Leukopenia
      White blood cell count
      White blood cell disorder
      Lymphocyte count abnormal
      Lymphocyte count decreased
      Lymphopenia
      NeutropeniaNeutrophil count decreased
      Febrile neutropenia
      Neutropenia
      Neutrophil count abnormal
      Pancytopenia or bone marrow failurePancytopenia
      Bone marrow failure
      Blood count abnormal
      Full blood count decreased
      Peripheral edemaLymphoedema
      Generalised oedema
      Oedema peripheral
      Peripheral swelling
      Pulmonary toxicityDyspnoea
      Pneumonia
      Renal toxicityAcute kidney injury
      Renal failure acute
      Renal disorder
      Renal impairment
      Renal failure
      Haematuria
      Blood creatinine increased
      Abbreviations: MedDRA PT = Medical Dictionary for Regulatory Activities preferred term.
      Figure thumbnail figs1
      Supplemental Figure 1Flow Diagram of FAERS Case Selection
      Abbreviations: FAERS = United States Food and Drug Administration Adverse Events Reporting System; Q = quarter.

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