SIR-SPHERES® Y-90 RESIN MICROSPHERES
Report
- Report Number
- 3005579300-2020-00001
- Event Type
- Death
- Date Received
- January 9, 2020
- Date of Event
- November 11, 2019
- Report Date
- March 6, 2020
- Manufacturer
- SIRTEX TECHNOLOGY PTY LTD / SIRTEX MEDICAL LIMITED
- Product Code
- NAW
- Adverse Event
- Yes
- Report Source
- Manufacturer report
- Reporter Location
- FR
- Reporter Occupation
- OTHER
Narratives
SENDER'S COMMENTS: THE ADVERSE EVENTS OF ICTERUS AND FEVER WERE CLASSIFIED AS SERIOUS SINCE THEY REQUIRED HOSPITALIZATION OF A 78-YEAR OLD MALE PATIENT. THE EVENTS OCCURRED ABOUT 4 MONTHS AFTER IMPLANTATION OF SIR-SPHERES MICROSPHERES AND 3 WEEKS AFTER START OF 5TH CHEMOTHERAPY CYCLE. FEVER IS EXPECTED FOR CHEMOTHERAPY AND CONSIDERED UNEXPECTED FOR SIR-SPHERES MICROSPHERES AND RELATED PROCEDURES AS FEVER IS EXPECTED TO OCCUR SHORTLY AFTER IMPLANTATION. ICTERUS (IN TERMS OF JAUNDICE) IS EXPECTED FOR SIR-SPHERES MICROSPHERES AND UNEXPECTED FOR RELATED PROCEDURES AND FOR CHEMOTHERAPY. THE TEMPORAL RELATIONSHIP OF THE EVENTS IS IMPLAUSIBLE REGARDING MAPPING AND IMPLANT PROCEDURES AND GEMCITABINE CONSIDERING ITS SHORT ELIMINATION HALF-LIFE AND PLAUSIBLE REGARDING CISPLATIN AND SIR-SPHERES MICROSPHERES CONSIDERING LATENCY EFFECTS. OF NOTE, THE ELDERLY PATIENT WHO PRESENTED WITH ICTERUS HAD BEEN ADMITTED WITH DISRUPTION OF LIVER FUNCTION AND ACUTE RENAL FAILURE AND DEVELOPMENT OF ALL THESE ISSUES MAY BE PROMOTED BY HIS UNDERLYING INTRAHEPATIC CHOLANGIOCARCINOMA. IN ADDITION, HIS CONCOMITANT MEDICATION INCLUDING VALSARTAN/HYDROCHLOROTHIAZIDE IN RARE CASES CAN ALSO BE ASSOCIATED WITH THE DEVELOPMENT OF ICTERUS AND FEVER. THE INVESTIGATOR ASSESSED THE EVENTS AS NOT RELATED TO CHEMOTHERAPY, SIR-SPHERES MICROSPHERES AND RELATED PROCEDURES. BASED ON THE INFORMATION AVAILABLE AND CONSIDERING THE UNDERLYING MALIGNANT DISEASE AS PLAUSIBLE ALTERNATIVE EXPLANATION, THE SPONSOR ASSESSES ICTERUS AS UNLIKELY RELATED AND FEVER AS NOT RELATED TO SIR-SPHERES MICROSPHERES AND BOTH EVENTS AS NOT RELATED TO CHEMOTHERAPY AND MAPPING AND IMPLANT PROCEDURES. WITH FOLLOW-UP INFORMATION RECEIVED ON 16-DEC-2019 IT WAS CLARIFIED THAT THE INVESTIGATOR CONSIDERED THE EVENTS TO BE CAUSED BY RADIOEMBOLIZATION INDUCED LIVER DISEASE (REILD). USUALLY REILD OCCURS UP TO 8 WEEKS AFTER SIRT, HOWEVER LONGER LATENCY TIMES HAVE BEEN OBSERVED AND REILD IS CHARACTERISED CLINICALLY BY ICTERUS AND ASCITES WHICH WERE BOTH OBSERVED IN THIS PATIENT. LIVER INJURY AND BOTH RENAL FAILURE, WHICH CAN BE PROMOTED BY SIRT AS WELL AS THE UNDERLYING MALIGNANT DISEASE AND CISPLATIN, CAN BE ASSOCIATED WITH LOW ALBUMIN, WHICH CAN MANIFEST WITH LOWER LIMB OEDEMA AND PLEURAL EFFUSION. THUS, OVERALL, FACTORS INVOLVING BOTH THE UNDERLYING DISEASE AND REILD MAY HAVE PROMOTED THE PATIENT'S SYMPTOMS. BASED ON THE NEWLY PROVIDED INFORMATION, THE SPONSOR CHANGES THE CAUSALITY OF ICTERUS FROM UNLIKELY TO POSSIBLY RELATED TO SIR-SPHERES MICROSPHERES. FOR CHEMOTHERAPY, MAPPING AND IMPLANT PROCEDURES THE CAUSALITY ASSESSMENT REMAINS UNCHANGED AS NOT RELATED. THE INVESTIGATOR'S CAUSALITY ASSESSMENT REMAINS UNCHANGED. WITH FOLLOW-UP INFORMATION RECEIVED ON (B)(6)2020 THE EVENTS ICTERUS AND FEVER WERE REPLACED BY THE EVENT RADIATION-INDUCED LIVER DISEASE (VERBATIM: REILD). THE EVENT IS EXPECTED FOR SIR-SPHERES MICROSPHERES AND UNEXPECTED FOR CHEMOTHERAPY PROCEDURES. THE TEMPORAL RELATIONSHIP IS CONSIDERED PLAUSIBLE FOR SIR-SPHERES MICROSPHERES AND CHEMOTHERAPY AND IMPLAUSIBLE FOR THE PROCEDURES. USUALLY REILD OCCURS 4-8 WEEKS AFTER SIRT, HOWEVER A LONGER TIME TO ONSET BETWEEN SIRT AND REILD RANGING UP TO 7 MONTHS HAS BEEN OBSERVED (BENSON ET AL., 2015). IN ADDITION, THE CLINICAL AND BIOCHEMICAL PICTURE OBSERVED IS CONSISTENT WITH WHAT IS EXPECTED FOR REILD. THE EVENT CLINICALLY MANIFESTS WITH JAUNDICE AND ASCITES AS SEEN IN THIS PATIENT. IN ADDITION, THE EVENT IS BIOCHEMICALLY CHARACTERIZED BY AN INCREASE OF BILIRUBIN, AN INCREASE OF ALP AND GGT AND NO CHANGE IN TRANSAMINASES, WHICH WAS ALSO THE CASE IN THIS PATIENT ALTHOUGH BILIRUBIN WAS BELOW 3 MG/DL AS TYPICALLY SEEN. THE EVENT WAS ACCOMPANIED BY PLEURAL EFFUSION IN THE CONTEXT OF ASCITIC DECOMPENSATION AND RENAL FAILURE DUE TO HEPATORENAL SYNDROME, WHICH IS ALSO EXPECTED FOR SIR-SPHERES. THE INVESTIGATOR ASSESSED THE EVENT AS PROBABLY RELATED TO SIR-SPHERES MICROSPHERES AND NOT RELATED TO PROCEDURES AND CHEMOTHERAPY. BASED ON THE INFORMATION AVAILABLE, THE SPONSOR CONCURS AND ASSESSES THE EVENT AS RELATED TO SIR-SPHERES MICROSPHERES AND NOT RELATED TO PROCEDURES AND CHEMOTHERAPY. WITH FOLLOW-UP INFORMATION RECEIVED ON (B)(6)2020 REILD WAS REPORTED AS ONGOING. NO CAUSE WAS IDENTIFIED EXPLAINING THE FEVER. OVERALL, THE CAUSALITY ASSESSMENT REMAINS UNCHANGED. WITH FOLLOW-UP INFORMATION RECEIVED ON (B)(6)2020 THE SERIOUSNESS CRITERION PATIENT DIED WAS ADDED AS IT WAS CLARIFIED THAT THE EVENT HAD A FATAL OUTCOME. REILD WITH FATAL OUTCOME IS EXPECTED FOR SIR-SPHERES MICROSPHERES AND REMAINS UNEXPECTED FOR PROCEDURES AND CHEMOTHERAPY. OF NOTE, THE EVENT WAS ACCOMPANIED BY ASCITIC DECOMPENSATION AND HEPATORENAL SYNDROME AND THE PATIENT'S ADVANCED AGE AND UNDERLYING INTRAHEPATIC CHOLANGIOCARCINOMA MAY HAVE FURTHER FACILITATED THE FATAL COURSE OF THE EVENT. THE CAUSALITY ASSESSMENT REMAINS UNCHANGED AS RELATED TO SIR-SPHERES MICROSPHERES AND NOT RELATED TO PROCEDURES AND CHEMOTHERAPY. WITH FOLLOW-UP INFORMATION RECEIVED ON (B)(6)2020 THE START DATE OF THE EVENT WAS CONFIRMED. THE CAUSALITY ASSESSMENT REMAINS UNCHANGED.
SENDER'S COMMENTS: THE ADVERSE EVENTS OF ICTERUS AND FEVER WERE CLASSIFIED AS SERIOUS SINCE THEY REQUIRED HOSPITALIZATION OF A 78-YEAR OLD MALE PATIENT. THE EVENTS OCCURRED ABOUT 4 MONTHS AFTER IMPLANTATION OF SIR-SPHERES MICROSPHERES AND 3 WEEKS AFTER START OF 5TH CHEMOTHERAPY CYCLE. FEVER IS EXPECTED FOR CHEMOTHERAPY AND CONSIDERED UNEXPECTED FOR SIR-SPHERES MICROSPHERES AND RELATED PROCEDURES AS FEVER IS EXPECTED TO OCCUR SHORTLY AFTER IMPLANTATION. ICTERUS (IN TERMS OF JAUNDICE) IS EXPECTED FOR SIR-SPHERES MICROSPHERES AND UNEXPECTED FOR RELATED PROCEDURES AND FOR CHEMOTHERAPY. THE TEMPORAL RELATIONSHIP OF THE EVENTS IS IMPLAUSIBLE REGARDING MAPPING AND IMPLANT PROCEDURES AND GEMCITABINE CONSIDERING ITS SHORT ELIMINATION HALF-LIFE AND PLAUSIBLE REGARDING CISPLATIN AND SIR-SPHERES MICROSPHERES CONSIDERING LATENCY EFFECTS. OF NOTE, THE ELDERLY PATIENT WHO PRESENTED WITH ICTERUS HAD BEEN ADMITTED WITH DISRUPTION OF LIVER FUNCTION AND ACUTE RENAL FAILURE AND DEVELOPMENT OF ALL THESE ISSUES MAY BE PROMOTED BY HIS UNDERLYING INTRAHEPATIC CHOLANGIOCARCINOMA. IN ADDITION, HIS CONCOMITANT MEDICATION INCLUDING VALSARTAN/HYDROCHLOROTHIAZIDE IN RARE CASES CAN ALSO BE ASSOCIATED WITH THE DEVELOPMENT OF ICTERUS AND FEVER. THE INVESTIGATOR ASSESSED THE EVENTS AS NOT RELATED TO CHEMOTHERAPY, SIR-SPHERES MICROSPHERES AND RELATED PROCEDURES. BASED ON THE INFORMATION AVAILABLE AND CONSIDERING THE UNDERLYING MALIGNANT DISEASE AS PLAUSIBLE ALTERNATIVE EXPLANATION, THE SPONSOR ASSESSES ICTERUS AS UNLIKELY RELATED AND FEVER AS NOT RELATED TO SIR-SPHERES MICROSPHERES AND BOTH EVENTS AS NOT RELATED TO CHEMOTHERAPY AND MAPPING AND IMPLANT PROCEDURES. WITH FOLLOW-UP INFORMATION RECEIVED ON 16-DEC-2019 IT WAS CLARIFIED THAT THE INVESTIGATOR CONSIDERED THE EVENTS TO BE CAUSED BY RADIOEMBOLIZATION INDUCED LIVER DISEASE (REILD). USUALLY REILD OCCURS UP TO 8 WEEKS AFTER SIRT, HOWEVER LONGER LATENCY TIMES HAVE BEEN OBSERVED AND REILD IS CHARACTERISED CLINICALLY BY ICTERUS AND ASCITES WHICH WERE BOTH OBSERVED IN THIS PATIENT. LIVER INJURY AND BOTH RENAL FAILURE, WHICH CAN BE PROMOTED BY SIRT AS WELL AS THE UNDERLYING MALIGNANT DISEASE AND CISPLATIN, CAN BE ASSOCIATED WITH LOW ALBUMIN, WHICH CAN MANIFEST WITH LOWER LIMB OEDEMA AND PLEURAL EFFUSION. THUS, OVERALL, FACTORS INVOLVING BOTH THE UNDERLYING DISEASE AND REILD MAY HAVE PROMOTED THE PATIENT'S SYMPTOMS. BASED ON THE NEWLY PROVIDED INFORMATION, THE SPONSOR CHANGES THE CAUSALITY OF ICTERUS FROM UNLIKELY TO POSSIBLY RELATED TO SIR-SPHERES MICROSPHERES. FOR CHEMOTHERAPY, MAPPING AND IMPLANT PROCEDURES THE CAUSALITY ASSESSMENT REMAINS UNCHANGED AS NOT RELATED. THE INVESTIGATOR'S CAUSALITY ASSESSMENT REMAINS UNCHANGED. WITH FOLLOW-UP INFORMATION RECEIVED ON 07-JAN-2020 THE EVENTS ICTERUS AND FEVER WERE REPLACED BY THE EVENT RADIATION-INDUCED LIVER DISEASE (VERBATIM: REILD). THE EVENT IS EXPECTED FOR SIR-SPHERES MICROSPHERES AND UNEXPECTED FOR CHEMOTHERAPY PROCEDURES. THE TEMPORAL RELATIONSHIP IS CONSIDERED PLAUSIBLE FOR SIR-SPHERES MICROSPHERES AND CHEMOTHERAPY AND IMPLAUSIBLE FOR THE PROCEDURES. USUALLY REILD OCCURS 4-8 WEEKS AFTER SIRT, HOWEVER A LONGER TIME TO ONSET BETWEEN SIRT AND REILD RANGING UP TO 7 MONTHS HAS BEEN OBSERVED (BENSON ET AL., 2015). IN ADDITION, THE CLINICAL AND BIOCHEMICAL PICTURE OBSERVED IS CONSISTENT WITH WHAT IS EXPECTED FOR REILD. THE EVENT CLINICALLY MANIFESTS WITH JAUNDICE AND ASCITES AS SEEN IN THIS PATIENT. IN ADDITION, THE EVENT IS BIOCHEMICALLY CHARACTERIZED BY AN INCREASE OF BILIRUBIN, AN INCREASE OF ALP AND GGT AND NO CHANGE IN TRANSAMINASES, WHICH WAS ALSO THE CASE IN THIS PATIENT ALTHOUGH BILIRUBIN WAS BELOW 3 MG/DL AS TYPICALLY SEEN. THE EVENT WAS ACCOMPANIED BY PLEURAL EFFUSION IN THE CONTEXT OF ASCITIC DECOMPENSATION AND RENAL FAILURE DUE TO HEPATORENAL SYNDROME, WHICH IS ALSO EXPECTED FOR SIR-SPHERES. THE INVESTIGATOR ASSESSED THE EVENT AS PROBABLY RELATED TO SIR-SPHERES MICROSPHERES AND NOT RELATED TO PROCEDURES AND CHEMOTHERAPY. BASED ON THE INFORMATION AVAILABLE, THE SPONSOR CONCURS AND ASSESSES THE EVENT AS RELATED TO SIR-SPHERES MICROSPHERES AND NOT RELATED TO PROCEDURES AND CHEMOTHERAPY.
SENDER'S COMMENTS: THE ADVERSE EVENTS OF ICTERUS AND FEVER WERE CLASSIFIED AS SERIOUS SINCE THEY REQUIRED HOSPITALIZATION OF A 78-YEAR OLD MALE PATIENT. THE EVENTS OCCURRED ABOUT 4 MONTHS AFTER IMPLANTATION OF SIR-SPHERES MICROSPHERES AND 3 WEEKS AFTER START OF 5TH CHEMOTHERAPY CYCLE. FEVER IS EXPECTED FOR CHEMOTHERAPY AND CONSIDERED UNEXPECTED FOR SIR-SPHERES MICROSPHERES AND RELATED PROCEDURES AS FEVER IS EXPECTED TO OCCUR SHORTLY AFTER IMPLANTATION. ICTERUS (IN TERMS OF JAUNDICE) IS EXPECTED FOR SIR-SPHERES MICROSPHERES AND UNEXPECTED FOR RELATED PROCEDURES AND FOR CHEMOTHERAPY. THE TEMPORAL RELATIONSHIP OF THE EVENTS IS IMPLAUSIBLE REGARDING MAPPING AND IMPLANT PROCEDURES AND GEMCITABINE CONSIDERING ITS SHORT ELIMINATION HALF-LIFE AND PLAUSIBLE REGARDING CISPLATIN AND SIR-SPHERES MICROSPHERES CONSIDERING LATENCY EFFECTS. OF NOTE, THE ELDERLY PATIENT WHO PRESENTED WITH ICTERUS HAD BEEN ADMITTED WITH DISRUPTION OF LIVER FUNCTION AND ACUTE RENAL FAILURE AND DEVELOPMENT OF ALL THESE ISSUES MAY BE PROMOTED BY HIS UNDERLYING INTRAHEPATIC CHOLANGIOCARCINOMA. IN ADDITION, HIS CONCOMITANT MEDICATION INCLUDING VALSARTAN/HYDROCHLOROTHIAZIDE IN RARE CASES CAN ALSO BE ASSOCIATED WITH THE DEVELOPMENT OF ICTERUS AND FEVER. THE INVESTIGATOR ASSESSED THE EVENTS AS NOT RELATED TO CHEMOTHERAPY, SIR-SPHERES MICROSPHERES AND RELATED PROCEDURES. BASED ON THE INFORMATION AVAILABLE AND CONSIDERING THE UNDERLYING MALIGNANT DISEASE AS PLAUSIBLE ALTERNATIVE EXPLANATION, THE SPONSOR ASSESSES ICTERUS AS UNLIKELY RELATED AND FEVER AS NOT RELATED TO SIR-SPHERES MICROSPHERES AND BOTH EVENTS AS NOT RELATED TO CHEMOTHERAPY AND MAPPING AND IMPLANT PROCEDURES. WITH FOLLOW-UP INFORMATION RECEIVED ON 16-DEC-2019 IT WAS CLARIFIED THAT THE INVESTIGATOR CONSIDERED THE EVENTS TO BE CAUSED BY RADIOEMBOLIZATION INDUCED LIVER DISEASE (REILD). USUALLY REILD OCCURS UP TO 8 WEEKS AFTER SIRT, HOWEVER LONGER LATENCY TIMES HAVE BEEN OBSERVED AND REILD IS CHARACTERISED CLINICALLY BY ICTERUS AND ASCITES WHICH WERE BOTH OBSERVED IN THIS PATIENT. LIVER INJURY AND BOTH RENAL FAILURE, WHICH CAN BE PROMOTED BY SIRT AS WELL AS THE UNDERLYING MALIGNANT DISEASE AND CISPLATIN, CAN BE ASSOCIATED WITH LOW ALBUMIN, WHICH CAN MANIFEST WITH LOWER LIMB OEDEMA AND PLEURAL EFFUSION. THUS, OVERALL, FACTORS INVOLVING BOTH THE UNDERLYING DISEASE AND REILD MAY HAVE PROMOTED THE PATIENT'S SYMPTOMS. BASED ON THE NEWLY PROVIDED INFORMATION, THE SPONSOR CHANGES THE CAUSALITY OF ICTERUS FROM UNLIKELY TO POSSIBLY RELATED TO SIR-SPHERES MICROSPHERES. FOR CHEMOTHERAPY, MAPPING AND IMPLANT PROCEDURES THE CAUSALITY ASSESSMENT REMAINS UNCHANGED AS NOT RELATED. THE INVESTIGATOR'S CAUSALITY ASSESSMENT REMAINS UNCHANGED. WITH FOLLOW-UP INFORMATION RECEIVED ON 07-JAN-2020 THE EVENTS ICTERUS AND FEVER WERE REPLACED BY THE EVENT RADIATION-INDUCED LIVER DISEASE (VERBATIM: REILD). THE EVENT IS EXPECTED FOR SIR-SPHERES MICROSPHERES AND UNEXPECTED FOR CHEMOTHERAPY PROCEDURES. THE TEMPORAL RELATIONSHIP IS CONSIDERED PLAUSIBLE FOR SIR-SPHERES MICROSPHERES AND CHEMOTHERAPY AND IMPLAUSIBLE FOR THE PROCEDURES. USUALLY REILD OCCURS 4-8 WEEKS AFTER SIRT, HOWEVER A LONGER TIME TO ONSET BETWEEN SIRT AND REILD RANGING UP TO 7 MONTHS HAS BEEN OBSERVED (BENSON ET AL., 2015). IN ADDITION, THE CLINICAL AND BIOCHEMICAL PICTURE OBSERVED IS CONSISTENT WITH WHAT IS EXPECTED FOR REILD. THE EVENT CLINICALLY MANIFESTS WITH JAUNDICE AND ASCITES AS SEEN IN THIS PATIENT. IN ADDITION, THE EVENT IS BIOCHEMICALLY CHARACTERIZED BY AN INCREASE OF BILIRUBIN, AN INCREASE OF ALP AND GGT AND NO CHANGE IN TRANSAMINASES, WHICH WAS ALSO THE CASE IN THIS PATIENT ALTHOUGH BILIRUBIN WAS BELOW 3 MG/DL AS TYPICALLY SEEN. THE EVENT WAS ACCOMPANIED BY PLEURAL EFFUSION IN THE CONTEXT OF ASCITIC DECOMPENSATION AND RENAL FAILURE DUE TO HEPATORENAL SYNDROME, WHICH IS ALSO EXPECTED FOR SIR-SPHERES. THE INVESTIGATOR ASSESSED THE EVENT AS PROBABLY RELATED TO SIR-SPHERES MICROSPHERES AND NOT RELATED TO PROCEDURES AND CHEMOTHERAPY. BASED ON THE INFORMATION AVAILABLE, THE SPONSOR CONCURS AND ASSESSES THE EVENT AS RELATED TO SIR-SPHERES MICROSPHERES AND NOT RELATED TO PROCEDURES AND CHEMOTHERAPY. WITH FOLLOW-UP INFORMATION RECEIVED ON 27-JAN-2020 REILD WAS REPORTED AS ONGOING. NO CAUSE WAS IDENTIFIED EXPLAINING THE FEVER. OVERALL, THE CAUSALITY ASSESSMENT REMAINS UNCHANGED. WITH FOLLOW-UP INFORMATION RECEIVED ON 12-FEB-2020 THE SERIOUSNESS CRITERION PATIENT DIED WAS ADDED AS IT WAS CLARIFIED THAT THE EVENT HAD A FATAL OUTCOME. REILD WITH FATAL OUTCOME IS EXPECTED FOR SIR-SPHERES MICROSPHERES AND REMAINS UNEXPECTED FOR PROCEDURES AND CHEMOTHERAPY. OF NOTE, THE EVENT WAS ACCOMPANIED BY ASCITIC DECOMPENSATION AND HEPATORENAL SYNDROME AND THE PATIENT'S ADVANCED AGE AND UNDERLYING INTRAHEPATIC CHOLANGIOCARCINOMA MAY HAVE FURTHER FACILITATED THE FATAL COURSE OF THE EVENT. THE CAUSALITY ASSESSMENT REMAINS UNCHANGED AS RELATED TO SIR-SPHERES MICROSPHERES AND NOT RELATED TO PROCEDURES AND CHEMOTHERAPY. WITH FOLLOW-UP INFORMATION RECEIVED ON 17-FEB-2020 THE START DATE OF THE EVENT WAS CONFIRMED. THE CAUSALITY ASSESSMENT REMAINS UNCHANGED. WITH FOLLOW-UP INFORMATION RECEIVED ON 21-FEB-2020 FURTHER INFORMATION ON THE PATIENT'S COURSE WAS PROVIDED, INCLUDING EXAMINATION RESULTS AND TREATMENTS. THE PATIENT PRESENTED WITH ACUTE RENAL FAILURE, OEDEMA AND ASCITES AND RECEIVED TREATMENT INCLUDING ALBUMIN, FUROSEMIDE AND SPIRONOLACTONE AS WELL AS ASCITIC PUNCTURES. DIAGNOSTIC WORK-UP DID NOT REVEAL TUMOUR PROGRESSION AND A FALL IN TOTAL PROTEIN AND FACTOR V WAS OBSERVED, WHICH IMPROVED UNDER THERAPY. DURING HOSPITALIZATION THE PATIENT BECAME CONFUSED AND A HEPATIC ENCEPHALOPATHY WAS SUSPECTED, WHICH MAY HAVE OCCURRED IN THE CONTEXT OF DISRUPTION OF LIVER FUNCTION AND REILD. ABOUT 7 WEEKS PRIOR TO HIS DEATH THE PATIENT WAS TRANSFERRED TO A CONVALESCENCE FACILITY AND NO FURTHER DETAILS ON THE PATIENT'S COURSE THERE WERE AVAILABLE. OVERALL, THE CAUSALITY ASSESSMENT REMAINS UNCHANGED AS RELATED TO SIR-SPHERES MICROSPHERES AND NOT RELATED TO PROCEDURES AND CHEMOTHERAPY. WITH FOLLOW-UP INFORMATION RECEIVED ON 02-MAR-2020 IT WAS CLARIFIED THAT HEPATIC ENCEPHALOPATHY WAS NOT CONSIDERED AS AN ADDITIONAL SAE SINCE IT OCCURRED IN THE CONTEXT REILD. THE CAUSALITY ASSESSMENT REMAINS UNCHANGED.
THIS REPORT IS THE INITIAL REPORT TO FDA, BUT THE FOLLOW-UP 1 REPORT OF CASE (B)(4) (WITH FOLLOW-UP 1 THE SAE OF ICTERUS WAS ASSESSED AS POSSIBLY RELATED TO SIR-SPHERES MICROSPHERES MEDICAL DEVICE BY THE MANUFACTURER). THE FOLLOW-UP 2 COMBINES INFORMATION RECEIVED BETWEEN (B)(6)2020 AND (B)(6)2020. A SERIOUS ADVERSE EVENT REPORT, (CASE NUMBER (B)(4) ), WAS RECEIVED FROM AN INVESTIGATOR IN FRANCE REGARDING A MALE PATIENT (PATIENT NO. 03314-001) ENROLLED IN "A PROSPECTIVE, MULTICENTRE, RANDOMISED, CONTROLLED STUDY EVALUATING SIR-SPHERES® Y-90 RESIN MICROSPHERES PRECEDING STANDARD CISPLATIN-GEMCITABINE (CIS-GEM) CHEMOTHERAPY VERSUS CIS-GEM CHEMOTHERAPY ALONE AS FIRST-LINE TREATMENT OF PATIENTS WITH UNRESECTABLE INTRAHEPATIC CHOLANGIOCARCINOMA (SIRCCA)", STUDY CODE STX0115. INITIAL REPORT WAS RECEIVED ON (B)(6)2019: THE REPORTED EVENT TERMS WERE ICTERUS AND FEVER. AT THE TIME OF THE EVENT ONSET THE PATIENT WAS 78-YEAR-OLD. THE PATIENT'S MEDICAL HISTORY WAS SIGNIFICANT FOR UNRESECTABLE INTRAHEPATIC CHOLANGIOCARCINOMA, ARTERIAL HYPERTENSION AND OSTEOARTHRITIS (ALL ONGOING). CONCOMITANT MEDICATION INCLUDED COTAREG (VALSARTAN, HYDROCHLOROTHIAZIDE), TABLETS, TAKEN ORALLY FOR ARTERIAL HYPERTENSION (START DATE AND DOSE NOT REPORTED), SOLUPRED (PREDNISOLONE 21-METASULPHOBENZOATE SODIUM), TABLETS, 60 MG/ DAY, SINCE (B)(6)2019 FOR NAUSEA PROPHYLAXIS AND ZOPHREN (ONDANSETRON), SOLUTION, 8 MG/ DAY, IV, SINCE (B)(6)2019 FOR NAUSEA PROPHYLAXIS. ALL CONCOMITANT MEDICATIONS WERE ASSESSED AS NOT RELATED TO THE EVENTS. THE PATIENT RECEIVED A COMBINED TREATMENT MODALITY OF SIR-SPHERES MICROSPHERES + CIS-GEM CHEMOTHERAPY. MAPPING PROCEDURE WAS PERFORMED ON (B)(6)2019 . IMPLANTATION OF SIR-SPHERES MICROSPHERES (1.24 GBQ, BATCH NO. NG408V08) WAS PERFORMED ON (B)(6)2019 . THE EVENT OCCURRED AFTER CHEMOTHERAPY CYCLE 5, STARTED ON (B)(6)2019 . THE SECOND ADMINISTRATION WAS PERFORMED ON (B)(6)2019 . ON (B)(6)2019 , THE PATIENT WAS HOSPITALISED FOR DISRUPTION OF LIVER FUNCTION WITH CHILLS THE PREVIOUS WEEK AND ACUTE RENAL FAILURE. THE EVENTS WERE ASSESSED AS MODERATE (ICTERUS) AND SEVERE (FEVER). RELEVANT DIAGNOSTIC TESTS INCLUDED A URINE TEST (RESULTS NORMAL), A BLOOD CULTURE (STILL BEING ANALYZED AT THE TIME OF THE REPORT) AND CRP (170 ¿MOL/L). CHEMOTHERAPY REGIMEN WAS WITHDRAWN. AT THE TIME OF THE REPORT, BOTH EVENTS WERE ONGOING. FOLLOW-UP INFORMATION WAS RECEIVED ON (B)(6)2019: THE INVESTIGATOR DIAGNOSED RADIOEMBOLIZATION INDUCED LIVER DISEASE AS THE ORIGIN OF THE EVENTS. "DISRUPTION OF LIVER FUNCTION" AND "ACUTE RENAL NFAILURE" WERE NOT CONSIDERED AS SEPARATE SAES. THE FUNCTIONAL RENAL INSUFFICIENCY DID NOT IMPROVE DESPITE FILLING AT 1.5L PER DAY OF NACL AND PRESENCE OF OEDEMAS OF THE LOWER LIMBS WAS OBSERVED. ACCORDING TO NEPHROLOGISTS OPINION ALBUMIN FLASKS WERE TO BE ADMINISTERED DUE TO LOW ALBUMIN VALUES (18 G/L). THE PRESENCE OF A SIGNIFICANT ASCITES WAS OBSERVED, AN EXPLORATORY PUNCTURE WAS NEGATIVE FOR ASCITES FLUID INFECTION AND BACTERIOSIS. INTRODUCTION OF 20 MG LASILIX (FUROSEMIDE) IN FRONT OF OEDEMA AND ASCITES ON (B)(6)2019 WITH REGULAR RENAL FUNCTION MONITORING. SECONDARY ADDITION OF SPIRONOLACTONE. DELAYED LIVER FUNCTION INJURY SECONDARY TO RADIO EMBOLIZATION (RILD) WAS EVOKED, SO A FLUIMICIL (ACETYLCYSTEINE) PROTOCOL WAS STARTED WITH ADDITION OF URSODEOXYCHOLIC ACID. THE RESULTS OF THE BLOOD CULTURE ((B)(6)2019) WERE NEGATIVE. AN MRI PERFORMED ON (B)(6)2019 SHOWED PARTIAL HEPATIC TUMORAL RESPONSE WITH BILATERAL PLEURAL AND INTRAPERITONEAL PLEURAL EFFUSION BUT NO PORTAL THROMBOSIS OR EVIDENCE OF CARCINOMATOSIS. CA19-9 VALUES WERE MEASURED ON (B)(6)2019 (234.2 U/ML) AND (B)(6)2019 (134 U/ML) ALONG WITH ACE VALUES (4.9 G/L AND 3.7 G/L RESPECTIVELY). THE OUTCOME FOR BOTH EVENTS REMAINED UNCHANGED AS ONGOING. FOLLOW-UP INFORMATION WAS RECEIVED ON (B)(6)2020: THE INVESTIGATOR CONFIRMED THE SAE OF "REILD" INSTEAD OF ICTERUS AND FEVER. THE DIAGNOSIS OF REILD WAS NOT BASED ON A LIVER BIOPSY, BUT WAS MADE BASED ON BIOLOGICAL AND RADIOLOGICAL RESULTS AND ALSO DUE TO THE TIME OF OCCURRENCE OF THE EVENT AFTER IMPLANTATION OF SIR-SPHERES MICROSPHERES. RELEVANT TEST RESULTS (PRIOR TO SIRT AND RECENT) SHOWED ASPARTATE AMINOTRANSFERASE (REFERENCE RANGE 10-50 U/L) ON (B)(6)2019=47 U/L, ON (B)(6)2019=83 U/L, AND ON (B)(6)2019=49 U/L. ALANINE AMINOTRANSFERASE (REFERENCE RANGE 10-50 U/I) ON (B)(6)2019=34 U/L, ON (B)(6)2019=41 U/L, AND ON (B)(6)2019=29 U/L. GAMMA-GLUTAMYL TRANSFERASE (REFERENCE RANGE 8-61 U/L) ON (B)(6)2019=91 U/L, ON (B)(6)2019 =399 U/L, AND ON (B)(6)2019=62 U/L. ALKALINE PHOSPHATASE (REFERENCE RANGE 40-130 U/L) ON (B)(6)2019=92 U/L, ON (B)(6)2019=239 U/L, AND ON (B)(6)2019=143 U/L. BILIRUBIN (REFERENCE RANGE <21 MOL/L) ON (B)(6)2019=7 MOL/L, ON (B)(6)2019=42 MOL/L, AND ON 17-(B)(6)2019=39 MOL/L. PLEURAL EFFUSION WAS CAUSED BY EDEMATOUS ASCITIC DECOMPENSATION, THE REASON FOR RENAL FAILURE WAS HEPATO-RENAL SYNDROME. NO CAUSE FOR FEVER WAS IDENTIFIED. AS OF (B)(6)2020 THE PATIENT HAD NOT RECOVERED. FOLLOW-UP INFORMATION WAS RECEIVED ON (B)(6)2020: THE INVESTIGATOR REPORTED THAT NO CAUSE WAS FOUND FOR THE FEVER OF THE PATIENT, AND THAT THE EVENT OF REILD WAS STILL ONGOING. FOLLOW-UP INFORMATION WAS RECEIVED ON (B)(6)2020: THE PATIENT PASSED AWAY ON (B)(6)2020, OUTCOME AND SEVERITY OF REILD WERE CHANGED TO FATAL. THE INVESTIGATOR PROVIDED THE SERIOUSNESS CRITERION "RESULTS IN DEATH". FURTHER CONCOMITANT MEDICATION INCLUDED FUROSEMIDE 40 MG TABLET, ORAL, STARTING (B)(6)2019 AND SPIRONOLACTONE, 75 MG TABLET, ORAL, STARTING (B)(6)2019 FOR EDEMA LIMBS. FOLLOW-UP INFORMATION WAS RECEIVED ON (B)(6)2020: THE INVESTIGATOR CONFIRMED (B)(6)2019 AS START DATE OF THE EVENT OF "REILD". REPORTER'S COMMENTS: THE INVESTIGATOR ASSESSED THE EVENTS AS NOT RELATED TO SIR-SPHERES MICROSPHERES (MAPPING PROCEDURE, IMPLANT PROCEDURE OR MEDICAL DEVICE), AND AS NOT RELATED TO CISPLATIN AND GEMCITABINE. FOLLOW-UP INFORMATION RECEIVED ON (B)(6)2020. THE INVESTIGATOR ASSESSED REILD AS NOT RELATED TO SIR-SPHERES MICROSPHERES (MAPPING AND IMPLANT PROCEDURE), AS PROBABLY/LIKELY RELATED TO SIR-SPHERES MICROSPHERES MEDICAL DEVICE AND AS NOT RELATED TO CISPLATIN AND GEMCITABINE.
THIS REPORT IS THE INITIAL REPORT TO FDA, BUT THE FOLLOW-UP 1 REPORT OF CASE (B)(4) (WITH FOLLOW-UP 1 THE SAE OF ICTERUS WAS ASSESSED AS POSSIBLY RELATED TO SIR-SPHERES MICROSPHERES MEDICAL DEVICE BY THE MANUFACTURER). A SERIOUS ADVERSE EVENT REPORT, (CASE NUMBER (B)(4)), WAS RECEIVED FROM AN INVESTIGATOR IN FRANCE REGARDING A MALE PATIENT (PATIENT NO. (B)(6)) ENROLLED IN "A PROSPECTIVE, MULTICENTRE, RANDOMISED, CONTROLLED STUDY EVALUATING SIR-SPHERES® Y-90 RESIN MICROSPHERES PRECEDING STANDARD CISPLATIN-GEMCITABINE (CIS-GEM) CHEMOTHERAPY VERSUS CIS-GEM CHEMOTHERAPY ALONE AS FIRST-LINE TREATMENT OF PATIENTS WITH UNRESECTABLE INTRAHEPATIC CHOLANGIOCARCINOMA (SIRCCA)", STUDY CODE STX0115. INITIAL REPORT WAS RECEIVED ON 12-NOV-2019: THE REPORTED EVENT TERMS WERE ICTERUS AND FEVER. AT THE TIME OF THE EVENT ONSET THE PATIENT WAS 78-YEAR-OLD. THE PATIENT'S MEDICAL HISTORY WAS SIGNIFICANT FOR UNRESECTABLE INTRAHEPATIC CHOLANGIOCARCINOMA, ARTERIAL HYPERTENSION AND OSTEOARTHRITIS (ALL ONGOING). CONCOMITANT MEDICATION INCLUDED COTAREG (VALSARTAN, HYDROCHLOROTHIAZIDE), TABLETS, TAKEN ORALLY FOR ARTERIAL HYPERTENSION (START DATE AND DOSE NOT REPORTED), SOLUPRED (PREDNISOLONE 21-METASULPHOBENZOATE SODIUM), TABLETS, 60 MG/ DAY, SINCE (B)(6) 2019 FOR NAUSEA PROPHYLAXIS AND ZOPHREN (ONDANSETRON), SOLUTION, 8 MG/ DAY, IV, SINCE(B)(6) 2019 FOR NAUSEA PROPHYLAXIS. ALL CONCOMITANT MEDICATIONS WERE ASSESSED AS NOT RELATED TO THE EVENTS. THE PATIENT RECEIVED A COMBINED TREATMENT MODALITY OF SIR-SPHERES MICROSPHERES + CIS-GEM CHEMOTHERAPY. MAPPING PROCEDURE WAS PERFORMED ON 09-JUL-2019. IMPLANTATION OF SIR-SPHERES MICROSPHERES (1.24 GBQ, BATCH NO. NG408V08) WAS PERFORMED ON (B)(6) 2019. THE EVENT OCCURRED AFTER CHEMOTHERAPY CYCLE 5, STARTED ON (B)(6) 2019. THE SECOND ADMINISTRATION WAS PERFORMED ON (B)(6) 2019. ON (B)(6) 2019, THE PATIENT WAS HOSPITALISED FOR DISRUPTION OF LIVER FUNCTION WITH CHILLS THE PREVIOUS WEEK AND ACUTE RENAL FAILURE. THE EVENTS WERE ASSESSED AS MODERATE (ICTERUS) AND SEVERE (FEVER). RELEVANT DIAGNOSTIC TESTS INCLUDED A URINE TEST (RESULTS NORMAL), A BLOOD CULTURE (STILL BEING ANALYZED AT THE TIME OF THE REPORT) AND CRP (170 MOL/L). CHEMOTHERAPY REGIMEN WAS WITHDRAWN. AT THE TIME OF THE REPORT, BOTH EVENTS WERE ONGOING. FOLLOW-UP INFORMATION WAS RECEIVED ON 16-DEC-2019: THE INVESTIGATOR DIAGNOSED RADIOEMBOLIZATION INDUCED LIVER DISEASE AS THE ORIGIN OF THE EVENTS. "DISRUPTION OF LIVER FUNCTION" AND "ACUTE RENAL NFAILURE" WERE NOT CONSIDERED AS SEPARATE SAES. THE FUNCTIONAL RENAL INSUFFICIENCY DID NOT IMPROVE DESPITE FILLING AT 1.5L PER DAY OF NACL AND PRESENCE OF OEDEMAS OF THE LOWER LIMBS WAS OBSERVED. ACCORDING TO NEPHROLOGISTS OPINION ALBUMIN FLASKS WERE TO BE ADMINISTERED DUE TO LOW ALBUMIN VALUES (18 G/L). THE PRESENCE OF A SIGNIFICANT ASCITES WAS OBSERVED, AN EXPLORATORY PUNCTURE WAS NEGATIVE FOR ASCITES FLUID INFECTION AND BACTERIOSIS. INTRODUCTION OF 20 MG LASILIX (FUROSEMIDE) IN FRONT OF OEDEMA AND ASCITES ON (B)(6) 2019 WITH REGULAR RENAL FUNCTION MONITORING. SECONDARY ADDITION OF SPIRONOLACTONE. DELAYED LIVER FUNCTION INJURY SECONDARY TO RADIO EMBOLIZATION (RILD) WAS EVOKED, SO A FLUIMICIL (ACETYLCYSTEINE) PROTOCOL WAS STARTED WITH ADDITION OF URSODEOXYCHOLIC ACID. THE RESULTS OF THE BLOOD CULTURE (07-NOV-2019) WERE NEGATIVE. AN MRI PERFORMED ON 19-NOV-2019 SHOWED PARTIAL HEPATIC TUMORAL RESPONSE WITH BILATERAL PLEURAL AND INTRAPERITONEAL PLEURAL EFFUSION BUT NO PORTAL THROMBOSIS OR EVIDENCE OF CARCINOMATOSIS. CA19-9 VALUES WERE MEASURED ON (B)(6) 2019 (234.2 U/ML) AND (B)(6) 2019 (134 U/ML) ALONG WITH ACE VALUES (4.9 G/L AND 3.7 G/L RESPECTIVELY). THE OUTCOME FOR BOTH EVENTS REMAINED UNCHANGED AS ONGOING. FOLLOW-UP INFORMATION WAS RECEIVED ON (B)(6) 2020: THE INVESTIGATOR CONFIRMED THE SAE OF "REILD" INSTEAD OF ICTERUS AND FEVER. THE DIAGNOSIS OF REILD WAS NOT BASED ON A LIVER BIOPSY, BUT WAS MADE BASED ON BIOLOGICAL AND RADIOLOGICAL RESULTS AND ALSO DUE TO THE TIME OF OCCURRENCE OF THE EVENT AFTER IMPLANTATION OF SIR-SPHERES MICROSPHERES. RELEVANT TEST RESULTS (PRIOR TO SIRT AND RECENT) SHOWED ASPARTATE AMINOTRANSFERASE (REFERENCE RANGE 10-50 U/L) ON (B)(6) 2019=47 U/L, ON (B)(6) 2019=83 U/L, AND ON (B)(6) 2019=49 U/L. ALANINE AMINOTRANSFERASE (REFERENCE RANGE 10-50 U/I) ON (B)(6) 2019=34 U/L, ON (B)(6) 2019=41 U/L, AND ON (B)(6) 2019=29 U/L. GAMMA-GLUTAMYL TRANSFERASE (REFERENCE RANGE 8-61 U/L) ON (B)(6) 2019=91 U/L, ON (B)(6) 2019=399 U/L, AND ON (B)(6) 2019=62 U/L. ALKALINE PHOSPHATASE (REFERENCE RANGE 40-130 U/L) ON (B)(6) 2019=92 U/L, ON (B)(6) 2019=239 U/L, AND ON (B)(6) 2019=143 U/L. BILIRUBIN (REFERENCE RANGE <21 MOL/L) ON (B)(6) 2019=7 MOL/L, ON (B)(6) 2019=42 MOL/L, AND ON (B)(6) 2019=39 MOL/L. PLEURAL EFFUSION WAS CAUSED BY EDEMATOUS ASCITIC DECOMPENSATION, THE REASON FOR RENAL FAILURE WAS HEPATO-RENAL SYNDROME. NO CAUSE FOR FEVER WAS IDENTIFIED. AS OF (B)(6) 2020 THE PATIENT HAD NOT RECOVERED. REPORTER'S COMMENTS: THE INVESTIGATOR ASSESSED THE EVENTS AS NOT RELATED TO SIR-SPHERES MICROSPHERES (MAPPING PROCEDURE, IMPLANT PROCEDURE OR MEDICAL DEVICE), AND AS NOT RELATED TO CISPLATIN AND GEMCITABINE. FOLLOW-UP INFORMATION RECEIVED ON 07-JAN-2020. THE INVESTIGATOR ASSESSED REILD AS NOT RELATED TO SIR-SPHERES MICROSPHERES (MAPPING AND IMPLANT PROCEDURE), AS PROBABLY/LIKELY RELATED TO SIR-SPHERES MICROSPHERES MEDICAL DEVICE AND AS NOT RELATED TO CISPLATIN AND GEMCITABINE.
THIS REPORT IS THE INITIAL REPORT TO FDA, BUT THE FOLLOW-UP 1 REPORT OF CASE (B)(4) (WITH FOLLOW-UP 1 THE SAE OF ICTERUS WAS ASSESSED AS POSSIBLY RELATED TO SIR-SPHERES MICROSPHERES MEDICAL DEVICE BY THE MANUFACTURER). THE FOLLOW-UP 2 COMBINES INFORMATION RECEIVED BETWEEN 27-JAN-2020 AND 17-FEB-2020. THE FOLLOW-UP 3 COMBINES INFORMATION RECEIVED ON 21-FEB-2020 AND 02-MAR-2020. A SERIOUS ADVERSE EVENT REPORT, (CASE NUMBER (B)(4)), WAS RECEIVED FROM AN INVESTIGATOR IN FRANCE REGARDING A MALE PATIENT (PATIENT NO.(B)(6)) ENROLLED IN "A PROSPECTIVE, MULTICENTRE, RANDOMISED, CONTROLLED STUDY EVALUATING SIR-SPHERES® Y-90 RESIN MICROSPHERES PRECEDING STANDARD CISPLATIN-GEMCITABINE (CIS-GEM) CHEMOTHERAPY VERSUS CIS-GEM CHEMOTHERAPY ALONE AS FIRST-LINE TREATMENT OF PATIENTS WITH UNRESECTABLE INTRAHEPATIC CHOLANGIOCARCINOMA (SIRCCA)", STUDY CODE STX0115. INITIAL REPORT WAS RECEIVED ON 12-NOV-2019: THE REPORTED EVENT TERMS WERE ICTERUS AND FEVER. AT THE TIME OF THE EVENT ONSET THE PATIENT WAS 78-YEAR-OLD. THE PATIENT'S MEDICAL HISTORY WAS SIGNIFICANT FOR UNRESECTABLE INTRAHEPATIC CHOLANGIOCARCINOMA, ARTERIAL HYPERTENSION AND OSTEOARTHRITIS (ALL ONGOING). CONCOMITANT MEDICATION INCLUDED COTAREG (VALSARTAN, HYDROCHLOROTHIAZIDE), TABLETS, TAKEN ORALLY FOR ARTERIAL HYPERTENSION (START DATE AND DOSE NOT REPORTED), SOLUPRED (PREDNISOLONE 21-METASULPHOBENZOATE SODIUM), TABLETS, 60 MG/ DAY, SINCE (B)(6) 2019 FOR NAUSEA PROPHYLAXIS AND ZOPHREN (ONDANSETRON), SOLUTION, 8 MG/ DAY, IV, SINCE (B)(6) 2019 FOR NAUSEA PROPHYLAXIS. ALL CONCOMITANT MEDICATIONS WERE ASSESSED AS NOT RELATED TO THE EVENTS. THE PATIENT RECEIVED A COMBINED TREATMENT MODALITY OF SIR-SPHERES MICROSPHERES + CIS-GEM CHEMOTHERAPY. MAPPING PROCEDURE WAS PERFORMED ON (B)(6) 2019. IMPLANTATION OF SIR-SPHERES MICROSPHERES (1.24 GBQ, BATCH NO. NG408V08) WAS PERFORMED ON (B)(6) 2019. THE EVENT OCCURRED AFTER CHEMOTHERAPY CYCLE 5, STARTED ON (B)(6) 2019. THE SECOND ADMINISTRATION WAS PERFORMED ON (B)(6) 2019. ON (B)(6) 2019, THE PATIENT WAS HOSPITALISED FOR DISRUPTION OF LIVER FUNCTION WITH CHILLS THE PREVIOUS WEEK AND ACUTE RENAL FAILURE. THE EVENTS WERE ASSESSED AS MODERATE (ICTERUS) AND SEVERE (FEVER). RELEVANT DIAGNOSTIC TESTS INCLUDED A URINE TEST (RESULTS NORMAL), A BLOOD CULTURE (STILL BEING ANALYZED AT THE TIME OF THE REPORT) AND CRP (170 MOL/L). CHEMOTHERAPY REGIMEN WAS WITHDRAWN. AT THE TIME OF THE REPORT, BOTH EVENTS WERE ONGOING. FOLLOW-UP INFORMATION WAS RECEIVED ON 16-DEC-2019: THE INVESTIGATOR DIAGNOSED RADIOEMBOLIZATION INDUCED LIVER DISEASE AS THE ORIGIN OF THE EVENTS. "DISRUPTION OF LIVER FUNCTION" AND "ACUTE RENAL NFAILURE" WERE NOT CONSIDERED AS SEPARATE SAES. THE FUNCTIONAL RENAL INSUFFICIENCY DID NOT IMPROVE DESPITE FILLING AT 1.5L PER DAY OF NACL AND PRESENCE OF OEDEMAS OF THE LOWER LIMBS WAS OBSERVED. ACCORDING TO NEPHROLOGISTS OPINION ALBUMIN FLASKS WERE TO BE ADMINISTERED DUE TO LOW ALBUMIN VALUES (18 G/L). THE PRESENCE OF A SIGNIFICANT ASCITES WAS OBSERVED, AN EXPLORATORY PUNCTURE WAS NEGATIVE FOR ASCITES FLUID INFECTION AND BACTERIOSIS. INTRODUCTION OF 20 MG LASILIX (FUROSEMIDE) IN FRONT OF OEDEMA AND ASCITES ON (B)(6) 2019 WITH REGULAR RENAL FUNCTION MONITORING. SECONDARY ADDITION OF SPIRONOLACTONE. DELAYED LIVER FUNCTION INJURY SECONDARY TO RADIO EMBOLIZATION (RILD) WAS EVOKED, SO A FLUIMICIL (ACETYLCYSTEINE) PROTOCOL WAS STARTED WITH ADDITION OF URSODEOXYCHOLIC ACID. THE RESULTS OF THE BLOOD CULTURE ((B)(6) 2019) WERE NEGATIVE. AN MRI PERFORMED ON (B)(6) 2019 SHOWED PARTIAL HEPATIC TUMORAL RESPONSE WITH BILATERAL PLEURAL AND INTRAPERITONEAL PLEURAL EFFUSION BUT NO PORTAL THROMBOSIS OR EVIDENCE OF CARCINOMATOSIS. CA19-9 VALUES WERE MEASURED ON (B)(6) 2019 (234.2 U/ML) AND (B)(6) 2019 (134 U/ML) ALONG WITH ACE VALUES (4.9 G/L AND 3.7 G/L RESPECTIVELY). THE OUTCOME FOR BOTH EVENTS REMAINED UNCHANGED AS ONGOING. FOLLOW-UP INFORMATION WAS RECEIVED ON 07-JAN-2020: THE INVESTIGATOR CONFIRMED THE SAE OF "REILD" INSTEAD OF ICTERUS AND FEVER. THE DIAGNOSIS OF REILD WAS NOT BASED ON A LIVER BIOPSY, BUT WAS MADE BASED ON BIOLOGICAL AND RADIOLOGICAL RESULTS AND ALSO DUE TO THE TIME OF OCCURRENCE OF THE EVENT AFTER IMPLANTATION OF SIR-SPHERES MICROSPHERES. RELEVANT TEST RESULTS (PRIOR TO SIRT AND RECENT) SHOWED ASPARTATE AMINOTRANSFERASE (REFERENCE RANGE 10-50 U/L) ON (B)(6) 2019=47 U/L, ON (B)(6) 2019=83 U/L, AND ON (B)(6) 2019=49 U/L. ALANINE AMINOTRANSFERASE (REFERENCE RANGE 10-50 U/I) ON (B)(6) 2019=34 U/L, ON (B)(6) 2019=41 U/L, AND ON (B)(6) 2019=29 U/L. GAMMA-GLUTAMYL TRANSFERASE (REFERENCE RANGE 8-61 U/L) ON (B)(6) 2019=91 U/L, ON (B)(6) 2019=399 U/L, AND ON (B)(6) 2019=62 U/L. ALKALINE PHOSPHATASE (REFERENCE RANGE 40-130 U/L) ON (B)(6) 2019=92 U/L, ON (B)(6) 2019=239 U/L, AND ON (B)(6) 2019=143 U/L. BILIRUBIN (REFERENCE RANGE <21 MOL/L) ON (B)(6) 2019=7 MOL/L, ON (B)(6) 2019=42 MOL/L, AND ON (B)(6) 2019=39 MOL/L. PLEURAL EFFUSION WAS CAUSED BY EDEMATOUS ASCITIC DECOMPENSATION, THE REASON FOR RENAL FAILURE WAS HEPATO-RENAL SYNDROME. NO CAUSE FOR FEVER WAS IDENTIFIED. AS OF (B)(6) 2020 THE PATIENT HAD NOT RECOVERED. FOLLOW-UP INFORMATION WAS RECEIVED ON 27-JAN-2020: THE INVESTIGATOR REPORTED THAT NO CAUSE WAS FOUND FOR THE FEVER OF THE PATIENT, AND THAT THE EVENT OF REILD WAS STILL ONGOING. FOLLOW-UP INFORMATION WAS RECEIVED ON 12-FEB-2020: THE PATIENT PASSED AWAY ON (B)(6) 2020, OUTCOME AND SEVERITY OF REILD WERE CHANGED TO FATAL. THE INVESTIGATOR PROVIDED THE SERIOUSNESS CRITERION "RESULTS IN DEATH". FURTHER CONCOMITANT MEDICATION INCLUDED FUROSEMIDE 40 MG TABLET, ORAL, STARTING (B)(6) 2019 AND SPIRONOLACTONE, 75 MG TABLET, ORAL, STARTING (B)(6) 2019 FOR EDEMA LIMBS. FOLLOW-UP INFORMATION WAS RECEIVED ON 17-FEB-2020: THE INVESTIGATOR CONFIRMED (B)(6) 2019 AS START DATE OF THE EVENT OF "REILD". FOLLOW-UP INFORMATION WAS RECEIVED ON 21-FEB-2020: THE INVESTIGATOR PROVIDED FURTHER INFORMATION ON THE COURSE OF REILD UNTIL DEATH. IN VIEW OF THE FUNCTIONAL PROFILE OF ACUTE RENAL FAILURE, AN ALBUMIN FILLING WAS PERFORMED AS PART OF THE TREATMENT OF THE PATIENT'S ACUTE RENAL FAILURE WHICH DID NOT RESPOND TO FILLING WITH SALINE SERUM. THE ALBUMIN FILLING COULD BE STOPPED ON (B)(6) 2019 AND THE PATIENT MAINTAINED NORMAL RENAL FUNCTION. THE PATIENT ALSO PRESENTED A TABLE OF ANASARCA ON ARRIVAL WITH EDEMAS OF THE LOWER LIMBS AND ASCITES, FOR WHICH LASILIX 40 MG WAS INTRODUCED AND SPIRONOLACTONE 50 MG WAS INCREASED TO 75 MG, OF MODERATE EFFECTIVENESS ON THE STATE OVERLOAD. IN FRONT OF THESE DISTURBANCES OF THE HEPATIC BALANCE A HEPATIC ECHOGRAPHY WAS INITIALLY CARRIED OUT SHOWING NO DILATION OF THE BILE DUCTS. A CT SCAN AND A LIVER MRI WERE PERFORMED WHICH SHOWED NO TUMOR PROGRESSION. THE ASCITES WAS PUNCTUATED AND HIGHLIGHTED A TRANSUDATIVE LIQUID INTEGRATING INTO AN ANASARCA TABLE, WITHOUT INFECTION OF THE ASCITES LIQUID OR BACTERIASCITA. AT THE SAME TIME, A GRADUAL FALL IN THE TP TO 20% WAS HIGHLIGHTED. THE FACTOR V FELL IN PARALLEL TO 60%. AFTER HEPATOLOGICAL OPINION ON THIS SERIOUS HEPATIC CELLULAR INSUFFICIENCY, WITHOUT ENCEPHALOPATHY, A REILD WAS EVOKED SECONDARY TO THE 2 SESSIONS OF RADIO EMBOLIZATION CARRIED OUT IN (B)(6). THEREFORE, A FLUIMICIL PROTOCOL WAS INTRODUCED ON (B)(6) 2019 AS WELL AS TREATMENT WITH CHOLURSO. THE TP AND FACTOR V THEN IMPROVED AND STABILIZED. ON (B)(6) 2019 THE PATIENT PRESENTED A STATE OF SLOWING DOWN WITH CONFUSION, WITHOUT TEMPORO-SPATIAL DISORIENTATION, WITHOUT FLAPPING OR REVERSAL OF THE NICTEMERAL RHYTHM. THE CEREBRAL CT WAS NORMAL AND A PROBABILISTIC TREATMENT WITH DUPHALAC WAS INTRODUCED IN FRONT OF THE STRONG SUSPICION OF HEPATIC ENCEPHALOPATHY. REGARDING THE PATIENT'S ASCITES, SEVERAL EVACUATION PUNCTURES WERE PERFORMED DURING HOSPITALIZATION, BRINGING AN AVERAGE 4 5L SYSTEMATICALLY COMPENSATED BY 1 OR 2 VIALS FOR 20 G OF ALBUMIN. THE PATIENT WAS HOSPITALIZED FROM (B)(6) 2019 THEN TRANSFERRED TO A CONVALESCENCE ESTABLISHMENT. THE INVESTIGATOR DID NOT RECEIVE FURTHER DETAILS ON THE PATIENT'S CARE SINCE THEN. FOLLOW-UP INFORMATION WAS RECEIVED ON 02-MAR-2020: THE INVESTIGATOR CONFIRMED THAT ONLY 1 RADIOEMBOLIZATION WAS CONDUCTED. THE REPORTED HEPATIC ENCEPHALOPATHY WAS NOT CONSIDERED AS FURTHER SAE BUT WAS DUE TO HEPATIC DECOMPENSATION INDUCED BY REILD. REPORTER'S COMMENTS: THE INVESTIGATOR ASSESSED THE EVENTS AS NOT RELATED TO SIR-SPHERES MICROSPHERES (MAPPING PROCEDURE, IMPLANT PROCEDURE OR MEDICAL DEVICE), AND AS NOT RELATED TO CISPLATIN AND GEMCITABINE. FOLLOW-UP INFORMATION RECEIVED ON 07-JAN-2020. THE INVESTIGATOR ASSESSED REILD AS NOT RELATED TO SIR-SPHERES MICROSPHERES (MAPPING AND IMPLANT PROCEDURE), AS PROBABLY/LIKELY RELATED TO SIR-SPHERES MICROSPHERES MEDICAL DEVICE AND AS NOT RELATED TO CISPLATIN AND GEMCITABINE.
SENDER'S COMMENTS: THE ADVERSE EVENTS OF ICTERUS AND FEVER WERE CLASSIFIED AS SERIOUS SINCE THEY REQUIRED HOSPITALIZATION OF A (B)(6)-YEAR OLD MALE PATIENT. THE EVENTS OCCURRED ABOUT 4 MONTHS AFTER IMPLANTATION OF SIR-SPHERES MICROSPHERES AND 3 WEEKS AFTER START OF 5TH CHEMOTHERAPY CYCLE. FEVER IS EXPECTED FOR CHEMOTHERAPY AND CONSIDERED UNEXPECTED FOR SIR-SPHERES MICROSPHERES AND RELATED PROCEDURES AS FEVER IS EXPECTED TO OCCUR SHORTLY AFTER IMPLANTATION. ICTERUS (IN TERMS OF JAUNDICE) IS EXPECTED FOR SIR-SPHERES MICROSPHERES AND UNEXPECTED FOR RELATED PROCEDURES AND FOR CHEMOTHERAPY. THE TEMPORAL RELATIONSHIP OF THE EVENTS IS IMPLAUSIBLE REGARDING MAPPING AND IMPLANT PROCEDURES AND GEMCITABINE CONSIDERING ITS SHORT ELIMINATION HALF-LIFE AND PLAUSIBLE REGARDING CISPLATIN AND SIR-SPHERES MICROSPHERES CONSIDERING LATENCY EFFECTS. OF NOTE, THE ELDERLY PATIENT WHO PRESENTED WITH ICTERUS HAD BEEN ADMITTED WITH DISRUPTION OF LIVER FUNCTION AND ACUTE RENAL FAILURE AND DEVELOPMENT OF ALL THESE ISSUES MAY BE PROMOTED BY HIS UNDERLYING INTRAHEPATIC CHOLANGIOCARCINOMA. IN ADDITION, HIS CONCOMITANT MEDICATION INCLUDING VALSARTAN/HYDROCHLOROTHIAZIDE IN RARE CASES CAN ALSO BE ASSOCIATED WITH THE DEVELOPMENT OF ICTERUS AND FEVER. THE INVESTIGATOR ASSESSED THE EVENTS AS NOT RELATED TO CHEMOTHERAPY, SIR-SPHERES MICROSPHERES AND RELATED PROCEDURES. BASED ON THE INFORMATION AVAILABLE AND CONSIDERING THE UNDERLYING MALIGNANT DISEASE AS PLAUSIBLE ALTERNATIVE EXPLANATION, THE SPONSOR ASSESSES ICTERUS AS UNLIKELY RELATED AND FEVER AS NOT RELATED TO SIR-SPHERES MICROSPHERES AND BOTH EVENTS AS NOT RELATED TO CHEMOTHERAPY AND MAPPING AND IMPLANT PROCEDURES. WITH FOLLOW-UP INFORMATION RECEIVED ON 16-DEC-2019 IT WAS CLARIFIED THAT THE INVESTIGATOR CONSIDERED THE EVENTS TO BE CAUSED BY RADIOEMBOLIZATION INDUCED LIVER DISEASE (REILD). USUALLY REILD OCCURS UP TO 8 WEEKS AFTER SIRT, HOWEVER LONGER LATENCY TIMES HAVE BEEN OBSERVED AND REILD IS CHARACTERISED CLINICALLY BY ICTERUS AND ASCITES WHICH WERE BOTH OBSERVED IN THIS PATIENT. LIVER INJURY AND BOTH RENAL FAILURE, WHICH CAN BE PROMOTED BY SIRT AS WELL AS THE UNDERLYING MALIGNANT DISEASE AND CISPLATIN, CAN BE ASSOCIATED WITH LOW ALBUMIN, WHICH CAN MANIFEST WITH LOWER LIMB OEDEMA AND PLEURAL EFFUSION. THUS, OVERALL, FACTORS INVOLVING BOTH THE UNDERLYING DISEASE AND REILD MAY HAVE PROMOTED THE PATIENT'S SYMPTOMS. BASED ON THE NEWLY PROVIDED INFORMATION, THE SPONSOR CHANGES THE CAUSALITY OF ICTERUS FROM UNLIKELY TO POSSIBLY RELATED TO SIR-SPHERES MICROSPHERES. FOR CHEMOTHERAPY, MAPPING AND IMPLANT PROCEDURES THE CAUSALITY ASSESSMENT REMAINS UNCHANGED AS NOT RELATED. THE INVESTIGATOR'S CAUSALITY ASSESSMENT REMAINS UNCHANGED.
THIS REPORT IS THE INITIAL REPORT TO FDA, BUT THE FOLLOW-UP 1 REPORT OF CASE (B)(4) (WITH FOLLOW-UP 1 THE SAE OF ICTERUS WAS ASSESSED AS POSSIBLY RELATED TO SIR-SPHERES MICROSPHERES MEDICAL DEVICE BY THE MANUFACTURER). A SERIOUS ADVERSE EVENT REPORT, (CASE NUMBER (B)(4)), WAS RECEIVED FROM AN INVESTIGATOR IN (B)(6) REGARDING A MALE PATIENT (PATIENT NO. (B)(6)) ENROLLED IN (B)(6), STUDY CODE (B)(4). INITIAL REPORT WAS RECEIVED ON 12-NOV-2019: THE REPORTED EVENT TERMS WERE ICTERUS AND FEVER. AT THE TIME OF THE EVENT ONSET THE PATIENT WAS (B)(6)-YEAR-OLD. THE PATIENT'S MEDICAL HISTORY WAS SIGNIFICANT FOR UNRESECTABLE INTRAHEPATIC CHOLANGIOCARCINOMA, ARTERIAL HYPERTENSION AND OSTEOARTHRITIS (ALL ONGOING). CONCOMITANT MEDICATION INCLUDED COTAREG (VALSARTAN, HYDROCHLOROTHIAZIDE), TABLETS, TAKEN ORALLY FOR ARTERIAL HYPERTENSION (START DATE AND DOSE NOT REPORTED), SOLUPRED (PREDNISOLONE 21-METASULPHOBENZOATE SODIUM), TABLETS, 60 MG/ DAY, SINCE (B)(6) 2019 FOR NAUSEA PROPHYLAXIS AND ZOPHREN (ONDANSETRON), SOLUTION, 8 MG/ DAY, IV, SINCE (B)(6) 2019 FOR NAUSEA PROPHYLAXIS. ALL CONCOMITANT MEDICATIONS WERE ASSESSED AS NOT RELATED TO THE EVENTS. THE PATIENT RECEIVED A COMBINED TREATMENT MODALITY OF SIR-SPHERES MICROSPHERES + CIS-GEM CHEMOTHERAPY. MAPPING PROCEDURE WAS PERFORMED ON (B)(6) 2019. IMPLANTATION OF SIR-SPHERES MICROSPHERES (1.24 GBQ, BATCH NO. NG408V08) WAS PERFORMED ON (B)(6) 2019. THE EVENT OCCURRED AFTER CHEMOTHERAPY CYCLE 5, STARTED ON (B)(6) 2019. THE SECOND ADMINISTRATION WAS PERFORMED ON (B)(6) 2019. ON (B)(6) 2019, THE PATIENT WAS HOSPITALISED FOR DISRUPTION OF LIVER FUNCTION WITH CHILLS THE PREVIOUS WEEK AND ACUTE RENAL FAILURE. THE EVENTS WERE ASSESSED AS MODERATE (ICTERUS) AND SEVERE (FEVER). RELEVANT DIAGNOSTIC TESTS INCLUDED A URINE TEST (RESULTS NORMAL), A BLOOD CULTURE (STILL BEING ANALYZED AT THE TIME OF THE REPORT) AND CRP (170 MOL/L). CHEMOTHERAPY REGIMEN WAS WITHDRAWN. AT THE TIME OF THE REPORT, BOTH EVENTS WERE ONGOING. FOLLOW-UP INFORMATION WAS RECEIVED ON 16-DEC-2019: THE INVESTIGATOR DIAGNOSED RADIOEMBOLIZATION INDUCED LIVER DISEASE AS THE ORIGIN OF THE EVENTS. "DISRUPTION OF LIVER FUNCTION" AND "ACUTE RENAL FAILURE" WERE NOT CONSIDERED AS SEPARATE SAES. THE FUNCTIONAL RENAL INSUFFICIENCY DID NOT IMPROVE DESPITE FILLING AT 1.5L PER DAY OF NACL AND PRESENCE OF OEDEMAS OF THE LOWER LIMBS WAS OBSERVED. ACCORDING TO NEPHROLOGISTS OPINION ALBUMIN FLASKS WERE TO BE ADMINISTERED DUE TO LOW ALBUMIN VALUES (18 G/L). THE PRESENCE OF A SIGNIFICANT ASCITES WAS OBSERVED, AN EXPLORATORY PUNCTURE WAS NEGATIVE FOR ASCITES FLUID INFECTION AND BACTERIOSIS. INTRODUCTION OF 20 MG LASILIX (FUROSEMIDE) IN FRONT OF OEDEMA AND ASCITES ON (B)(6) 2019 WITH REGULAR RENAL FUNCTION MONITORING. SECONDARY ADDITION OF SPIRONOLACTONE. DELAYED LIVER FUNCTION INJURY SECONDARY TO RADIO EMBOLIZATION (RILD) WAS EVOKED, SO A FLUIMICIL (ACETYLCYSTEINE) PROTOCOL WAS STARTED WITH ADDITION OF URSODEOXYCHOLIC ACID. THE RESULTS OF THE BLOOD CULTURE ((B)(6) 2019) WERE NEGATIVE. AN MRI PERFORMED ON (B)(6) 2019 SHOWED PARTIAL HEPATIC TUMORAL RESPONSE WITH BILATERAL PLEURAL AND INTRAPERITONEAL PLEURAL EFFUSION BUT NO PORTAL THROMBOSIS OR EVIDENCE OF CARCINOMATOSIS. CA19-9 VALUES WERE MEASURED ON (B)(6) 2019 (234.2 U/ML) AND (B)(6) 2019 (134 U/ML) ALONG WITH ACE VALUES (4.9 G/L AND 3.7 G/L RESPECTIVELY). THE OUTCOME FOR BOTH EVENTS REMAINED UNCHANGED AS ONGOING. REPORTER'S COMMENTS: THE INVESTIGATOR ASSESSED THE EVENTS AS NOT RELATED TO SIR-SPHERES MICROSPHERES (MAPPING PROCEDURE, IMPLANT PROCEDURE OR MEDICAL DEVICE), AND AS NOT RELATED TO CISPLATIN AND GEMCITABINE.
Devices
| Seq | Brand | Generic | Product Code | Manufacturer | Model | Lot | UDI-DI |
|---|---|---|---|---|---|---|---|
| 35096 | SIR-SPHERES® Y-90 RESIN MICROSPHERES | MICROSPHERES | NAW | SIRTEX TECHNOLOGY PTY LTD / SIRTEX MEDICAL LIMITED | NG408V08 |
Patients
| Seq | Age | Sex | Outcome | Treatment |
|---|---|---|---|---|
| 1 | 78 YR | Death| H | CISPLATIN| CISPLATIN| CISPLATIN| CISPLATIN| COTAREG| COTAREG| COTAREG| COTAREG| FUROSEMIDE| FUROSEMIDE| GEMCITABINE| GEMCITABINE| GEMCITABINE| GEMCITABINE| SOLUPRED| SOLUPRED| SOLUPRED| SOLUPRED| SPIRONOLACTONE| SPIRONOLACTONE| ZOPHREN| ZOPHREN| ZOPHREN| ZOPHREN |