| Lot Number LH415V03 |
| Device Problem
Insufficient Information (3190)
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| Patient Problems
Abdominal Pain (1685); Anemia (1706); Death (1802); Dyspnea (1816); Encephalopathy (1833); Erythema (1840); Hemorrhage/Bleeding (1888); High Blood Pressure/ Hypertension (1908); Unspecified Infection (1930); Pain (1994); Renal Failure (2041); Swelling (2091); Thrombus (2101); Vomiting (2144); Cognitive Changes (2551); Constipation (3274)
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| Event Date 12/19/2017 |
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Event Type
Death
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Manufacturer Narrative
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Serious adverse event of general physical health deterioration led to hospitalization of a (b)(6) female patient 28 days after the second administration of chemotherapy within cycle 4.Treatment with sir-spheres microspheres was not reported.The temporal relationship is considered plausible for cisplatin and gemcitabine.General physical health deterioration is unexpected for cisplatin and gemcitabine.The patient experienced multiple symptoms.Acute kidney failure is a known side effect of gemcitabine and cisplatin and it is known that gemcitabine might act hepatotoxically.Furthermore, both chemotherapeutics may cause asthenia promoting alteration of general state.However, the patient's underlying disease of unresectable intrahepatic cholangiocarcinoma also provides a plausible explanation for increasing signs of hepatocellular insufficiency contributing to deterioration of health.The investigator's assessment was not provided.Considering the plausible temporal course and the known safety profile of gemcitabine and cisplatin the sponsor assesses a contributing role of both chemotherapeutics to general physical health alteration as possible.With follow-up information received on 24-jan-2018 it was clarified that the patient received sir-spheres microspheres and the events blood bilirubin increased, platelet count decreased and encephalopathy were added.The adverse events of general physical health deterioration, blood bilirubin increased, platelet count increased and encephalopathy were classified as serious since they required hospitalization of an (b)(6) female patient about 17 weeks after mapping procedure, 16 weeks after sir-spheres microspheres implantation and 4 weeks after the second administration of chemotherapy within cycle 4.General physical health deterioration is unexpected for sir-spheres microspheres, mapping and implantation procedure and chemotherapy.Blood bilirubin increased and platelet count decreased are expected for cisplatin and gemcitabine and unexpected for sir-spheres microspheres and related procedures.Encephalopathy is unexpected for all imps and procedures.The temporal relationship is implausible for sir-spheres microspheres, mapping and implant procedure but plausible for cisplatin and gemcitabine regarding all events.Noteworthy, the patient also suffered from further issues, including ascites, elevation of liver values and creatinine, which might be indicative for progression of her malignant disease.Thus, her underlying cholangiocarcinoma may have promoted bilirubin increase and also encephalopathy considering a possible hepatic genesis (hepatic encephalopathy), however, etiology of encephalopathy was not provided.Furthermore, hepatic encephalopathy is a known side effect of the patient's concomitant medication of indapamide and furosemide.In addition, chemotherapy is known to cause bilirubin increase and platelet count decrease, which provides a likely alternative explanation for these events.Overall, all these events as well as the underlying malignant disease might have contributed to the patient's general physical health deterioration for which the outcome was provided as fatal.The investigator assessed general physical health deterioration as possibly related to sir-spheres microspheres, cisplatin and gemcitabine and as not related to mapping and implant procedure.Blood bilirubin increased, platelet count decreased, and encephalopathy were assessed as possibly related to sir-spheres microspheres and as not related to procedures and chemotherapy.Considering the implausible temporal course and the plausible alternative explanation, the events general physical health deterioration, blood bilirubin increased, platelet count decreased and encephalopathy are assessed as unlikely related to sir-spheres microspheres and not related to mapping and implant procedure.Based on known safety profile and plausible temporal course blood bilirubin increased and platelet count decreased are assessed as possibly related to cisplatin and gemcitabine, while encephalopathy is assessed as unlikely related to chemotherapy.The initial causality assessment for general physical health deterioration remains unchanged as possibly related to chemotherapy.With follow-up information received on 02-feb-2018 it was clarified that the patient died due to hepatocellular insufficiency, therefore the event hepatic insufficiency was added.In addition, the etiology for encephalopathy was provided as hepatocellular insufficiency.Thus, the event encephalopathy was amended to hepatic encephalopathy.The event hepatic insufficiency is expected for sir-spheres microspheres and gemcitabine and unexpected for cisplatin and mapping and implant procedure.The event hepatic encephalopathy is expected for sir-spheres microspheres and unexpected for mapping and implant procedure, cisplatin and gemcitabine, although hepatotoxicity is a known side effect of gemcitabine.No exact onset date for hepatocellular insufficiency was provided, however death due to the event occurred 4.5 months after mapping and implantation procedure and two months after latest chemotherapy administration.Considering latency time and cumulative effects, the temporal relationship of both hepatic insufficiency and hepatic encephalopathy is considered plausible for sir-spheres microspheres and for chemotherapy and implausible for sir-spheres microspheres procedures.The patient's underlying malignant disease provides a plausible explanation for both hepatic encephalopathy and insufficiency and the concomitant medication including indapamide and furosemide may have also promoted the events.The sponsor assessed the causality for hepatic encephalopathy and hepatic insufficiency as possibly related to sir-spheres microspheres and gemcitabine, unlikely related to cisplatin and not related to mapping and implant procedure.The sponsor's causality assessment for all other events remains unchanged.The investigator did not provide a causality assessment for hepatic insufficiency and the investigator's causality for all other events remains unchanged.With follow-up information received on 01-mar-2018 the investigator provided his causality assessment for the event hepatic insufficiency: probably related to sir-spheres microspheres, sir-spheres mapping and implant procedure and possibly related to gemcitabine and cisplatin.The sponsor's assessment remains unchanged, considering the temporal course and contributing factors: possibly related to sir-spheres microspheres and gemcitabine, unlikely related to cisplatin and not related to mapping and implant procedure.The causality assessment for all other events remains unchanged.
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Event Description
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This report combines information received between 22-dec-2017 and 01-mar-2018.This is the initial medical device report submitted to the fda.With follow-up information received on 24-jan-2018 the case classified as unanticipated serious adverse device effect report as the investigator provided information on sir-spheres microspheres treatment and included a causality assessment.A serious adverse event report ((b)(4)) was received on 22-dec-2017 from an investigator in france regarding a female patient, (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 (b)(6).The reported event term was general state alteration.The patient's medical history was significant for unresectable intrahepatic cholangiocarcinoma.Concomitant medication was not reported.The patient received a combined treatment modality (sir-spheres microspheres + cis-gem chemotherapy).The event occurred after chemotherapy cycle 4 started on (b)(6) 2017.The second administration was performed on (b)(6) 2017.On (b)(6) 2017, the patient presented with general state alteration, lower limb obliteration "majoration", erythema on the left lower limb, painful, without fever.Acute kidney failure and increasing biological signs of hepatocellular insufficiency were noted.The event was severe.The patient was hospitalised on (b)(6) 2017.The patient was not withdrawn from the study due to this event.At the time of the report, the event was ongoing and the patient's outcome was reported as "not recovered".Follow up information was received on 24-jan-2018.The investigator provided the following information regarding treatment with sir-spheres microspheres: mapping procedure was performed on (b)(6) 2017.Implantation of sir-spheres microspheres (1.479 gbq, batch no.Lh415v03) was performed on (b)(6) 2017 via right branch.Further medical history included hypertension, hypercholesterolemia, hypothyroidism, valvular leakage, edema limbs, and diabetes.Concomitant medication included: sotalex (sotalol hydrochloride), 160 mg daily, oral, from 2002 to (b)(6) 2018, for valvular leakage simvastatine, 20 mg daily, oral, from 2002 to (b)(6) 2018, for hypercholesterolemia levothyrox (levothyroxine), 75 mg daily, oral, from 2007 to (b)(6) 2018, for hypothyroidism indapamide, 1.5 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for hypertension amlodipine, 5 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for hypertension metformine, 2100 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for diabetes furosemide, 40 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for edema limbs.After hospitalisation due to general state alteration on (b)(6) 2017, the patient experienced further adverse events during hospitalisation: dyspnea, erythema, mucositis oral, erysipelas, ascites, oral hemorrhage, anemia, abdominal pain, constipation, vomiting, creatinine increased, aspartate aminotransferase (asat) increased, alanine aminotransferase (alat) increased, gamma-glutamyltransferase (ggt) increased, alkaline phosphatase (pal) increased, bloating and thromboembolic event.On (b)(6) 2017, the patient experienced the serious adverse events of blood bilirubin increased (severity: life-threatening) and encephalopathy (severity: severe).On (b)(6) 2017, the patient experienced the serious adverse event of platelet count decreased (severity: life-threatening).Relevant laboratory test results are provided as structured information.The patient was treated with albumin and ceftriaxone for ascites, sodium bicarbonate and fungizone (amphotericin b) for mucositis oral, duphalac (lactulose) and rifaximin for encephalopathy, amoxicillin for erysipelas, paracetamol, phloroglucinol, and oxycodone for abdominal pain, trimebutine for bloating, eductyl (potassium tartrate acid) for constipation, ondansetron for vomiting, platelet transfusion for platelet count decreased, and calciparine (heparin calcium) for thromboembolic event.The patient died on (b)(6) 2018.Follow up information received on 02-feb-2018: the investigator specified the reason for patient's encephalopathy and death as hepatocellular insufficiency.Further laboratory test result values taken on (b)(6) 2017 (before hospitalization) and (b)(6) 2018 were provided.Details are outlined in the structured information.Follow up information received on 01-mar-2018: the investigator clarified that he did not consider the seriousness criterion 'fatal' (results in death) applicable for the event term general state alteration.Furthermore, the cause of the death 'hepatobiliary insufficiency' was confirmed as separate sae and the seriousness criterion provided as 'fatal' (results in death).Reporter's comment: the investigator did not provide a causality assessment regarding the serious adverse event and chemotherapy agents.With follow-up information received on 24-jan-2018, the investigator assessed the sae of general state alteration as possibly related to sir-spheres microspheres (medical device), cisplatin and gemcitabine and as not related to sir-spheres microspheres (mapping and implant procedure).The saes of blood bilirubin increased, platelet count decreased, and encephalopathy were assessed as possibly related to sir-spheres microspheres (medical device) and as not related to sir-spheres microspheres (mapping and implant procedure), cisplatin and gemcitabine.With follow-up information received on 01-mar-2018, the investigator assessed the event hepatobiliary insufficiency as probable/likely related to sir-spheres microspheres device, sir-spheres microspheres mapping procedure, and sir-spheres microspheres implant procedure, and possibly related to cisplatin and gemcitabine.Please note, this report has also been submitted as an ide report (b)(4).
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Manufacturer Narrative
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Serious adverse event of general physical health deterioration led to hospitalization of a (b)(6) female patient 28 days after the second administration of chemotherapy within cycle 4.Treatment with sir-spheres microspheres was not reported.The temporal relationship is considered plausible for cisplatin and gemcitabine.General physical health deterioration is unexpected for cisplatin and gemcitabine.The patient experienced multiple symptoms.Acute kidney failure is a known side effect of gemcitabine and cisplatin and it is known that gemcitabine might act hepatotoxically.Furthermore, both chemotherapeutics may cause asthenia promoting alteration of general state.However, the patient's underlying disease of unresectable intrahepatic cholangiocarcinoma also provides a plausible explanation for increasing signs of hepatocellular insufficiency contributing to deterioration of health.The investigator's assessment was not provided.Considering the plausible temporal course and the known safety profile of gemcitabine and cisplatin the sponsor assesses a contributing role of both chemotherapeutics to general physical health alteration as possible.With follow-up information received on 24-jan-2018 it was clarified that the patient received sir-spheres microspheres and the events blood bilirubin increased, platelet count decreased and encephalopathy were added.The adverse events of general physical health deterioration, blood bilirubin increased, platelet count increased and encephalopathy were classified as serious since they required hospitalization of an (b)(6) female patient about 17 weeks after mapping procedure, 16 weeks after sir-spheres microspheres implantation and 4 weeks after the second administration of chemotherapy within cycle 4.General physical health deterioration is unexpected for sir-spheres microspheres, mapping and implantation procedure and chemotherapy.Blood bilirubin increased and platelet count decreased are expected for cisplatin and gemcitabine and unexpected for sir-spheres microspheres and related procedures.Encephalopathy is unexpected for all imps and procedures.The temporal relationship is implausible for sir-spheres microspheres, mapping and implant procedure but plausible for cisplatin and gemcitabine regarding all events.Noteworthy, the patient also suffered from further issues, including ascites, elevation of liver values and creatinine, which might be indicative for progression of her malignant disease.Thus, her underlying cholangiocarcinoma may have promoted bilirubin increase and also encephalopathy considering a possible hepatic genesis (hepatic encephalopathy), however, etiology of encephalopathy was not provided.Furthermore, hepatic encephalopathy is a known side effect of the patient's concomitant medication of indapamide and furosemide.In addition, chemotherapy is known to cause bilirubin increase and platelet count decrease, which provides a likely alternative explanation for these events.Overall, all these events as well as the underlying malignant disease might have contributed to the patient's general physical health deterioration for which the outcome was provided as fatal.The investigator assessed general physical health deterioration as possibly related to sir-spheres microspheres, cisplatin and gemcitabine and as not related to mapping and implant procedure.Blood bilirubin increased, platelet count decreased, and encephalopathy were assessed as possibly related to sir-spheres microspheres and as not related to procedures and chemotherapy.Considering the implausible temporal course and the plausible alternative explanation, the events general physical health deterioration, blood bilirubin increased, platelet count decreased and encephalopathy are assessed as unlikely related to sir-spheres microspheres and not related to mapping and implant procedure.Based on known safety profile and plausible temporal course blood bilirubin increased and platelet count decreased are assessed as possibly related to cisplatin and gemcitabine, while encephalopathy is assessed as unlikely related to chemotherapy.The initial causality assessment for general physical health deterioration remains unchanged as possibly related to chemotherapy.With follow-up information received on 02-feb-2018 it was clarified that the patient died due to hepatocellular insufficiency, therefore the event hepatic insufficiency was added.In addition, the etiology for encephalopathy was provided as hepatocellular insufficiency.Thus, the event encephalopathy was amended to hepatic encephalopathy.The event hepatic insufficiency is expected for sir-spheres microspheres and gemcitabine and unexpected for cisplatin and mapping and implant procedure.The event hepatic encephalopathy is expected for sir-spheres microspheres and unexpected for mapping and implant procedure, cisplatin and gemcitabine, although hepatotoxicity is a known side effect of gemcitabine.No exact onset date for hepatocellular insufficiency was provided, however death due to the event occurred 4.5 months after mapping and implantation procedure and two months after latest chemotherapy administration.Considering latency time and cumulative effects, the temporal relationship of both hepatic insufficiency and hepatic encephalopathy is considered plausible for sir-spheres microspheres and for chemotherapy and implausible for sir-spheres microspheres procedures.The patient's underlying malignant disease provides a plausible explanation for both hepatic encephalopathy and insufficiency and the concomitant medication including indapamide and furosemide may have also promoted the events.The sponsor assessed the causality for hepatic encephalopathy and hepatic insufficiency as possibly related to sir-spheres microspheres and gemcitabine, unlikely related to cisplatin and not related to mapping and implant procedure.The sponsor's causality assessment for all other events remains unchanged.The investigator did not provide a causality assessment for hepatic insufficiency and the investigator's causality for all other events remains unchanged.With follow-up information received on 01-mar-2018 the investigator provided his causality assessment for the event hepatic insufficiency: probably related to sir-spheres microspheres, sir-spheres mapping and implant procedure and possibly related to gemcitabine and cisplatin.The sponsor's assessment remains unchanged, considering the temporal course and contributing factors: possibly related to sir-spheres microspheres and gemcitabine, unlikely related to cisplatin and not related to mapping and implant procedure.The causality assessment for all other events remains unchanged.With follow-up information received on 15-mar-2018 the investigator clarified that hepatic insufficiency was considered as probably related to sir-spheres microspheres mapping and implantation and possibly related to cisplatin since the insufficiency occurred after transarterial radioembolization and chemotherapy without underlying liver disease.No further details, such as information on possible complications during the procedures was provided and considering the temporal course and underlying intrahepatic cholangiocarcinoma, the sponsor's causality assessment for hepatic insufficiency remains unchanged: possibly related to sir-spheres microspheres and gemcitabine, unlikely related to cisplatin and not related to mapping and implant procedure.By follow-up information received on 21-mar-2018 the investigator reported that no complications had occurred during sir-spheres microspheres mapping and implantation procedure.Therefore, the sponsor's causality assessment remains unchanged (possibly related to sir-spheres microspheres and gemcitabine, unlikely related to cisplatin and not related to mapping and implant procedure).
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Event Description
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This report combines information received between 22-dec-2017 and 01-mar-2018.This is the initial medical device report submitted to the fda.With follow-up information received on 24-jan-2018 the case classified as unanticipated serious adverse device effect report as the investigator provided information on sir-spheres microspheres treatment and included a causality assessment.A serious adverse event report (case (b)(4)) was received on 22-dec-2017 from an investigator in (b)(6) regarding a female patient, (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 (b)(6).The reported event term was general state alteration.The patient's medical history was significant for unresectable intrahepatic cholangiocarcinoma.Concomitant medication was not reported.The patient received a combined treatment modality (sir-spheres microspheres + cis-gem chemotherapy).The event occurred after chemotherapy cycle 4 started on (b)(6) 2017.The second administration was performed on (b)(6) 2017.On (b)(6) 2017, the patient presented with general state alteration, lower limb obliteration "majoration", erythema on the left lower limb, painful, without fever.Acute kidney failure and increasing biological signs of hepatocellular insufficiency were noted.The event was severe.The patient was hospitalised on (b)(6) 2017.The patient was not withdrawn from the study due to this event.At the time of the report, the event was ongoing and the patient's outcome was reported as "not recovered".Follow up information was received on 24-jan-2018.The investigator provided the following information regarding treatment with sir-spheres microspheres: mapping procedure was performed on (b)(6) 2017.Implantation of sir-spheres microspheres (1.479 gbq, batch no.Lh415v03) was performed on (b)(6) 2017 via right branch.Further medical history included hypertension, hypercholesterolemia, hypothyroidism, valvular leakage, edema limbs, and diabetes.Concomitant medication included: sotalex (sotalol hydrochloride), 160 mg daily, oral, from 2002 to (b)(6) 2018, for valvular leakage.Simvastatine, 20 mg daily, oral, from 2002 to (b)(6) 2018, for hypercholesterolemia.Levothyrox (levothyroxine), 75 mg daily, oral, from 2007 to (b)(6) 2018, for hypothyroidism.Indapamide, 1.5 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for hypertension.Amlodipine, 5 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for hypertension.Metformine, 2100 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for diabetes.Furosemide, 40 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for edema limbs.After hospitalisation due to general state alteration on (b)(6) 2017, the patient experienced further adverse events during hospitalisation: dyspnea, erythema, mucositis oral, erysipelas, ascites, oral hemorrhage, anemia, abdominal pain, constipation, vomiting, creatinine increased, aspartate aminotransferase (asat) increased, alanine aminotransferase (alat) increased, gamma-glutamyltransferase (ggt) increased, alkaline phosphatase (pal) increased, bloating and thromboembolic event.On (b)(6) 2017, the patient experienced the serious adverse events of blood bilirubin increased (severity: life-threatening) and encephalopathy (severity: severe).On (b)(6) 2017, the patient experienced the serious adverse event of platelet count decreased (severity: life-threatening).Relevant laboratory test results are provided as structured information.The patient was treated with albumin and ceftriaxone for ascites, sodium bicarbonate and fungizone (amphotericin b) for mucositis oral, duphalac (lactulose) and rifaximin for encephalopathy, amoxicillin for erysipelas, paracetamol, phloroglucinol, and oxycodone for abdominal pain, trimebutine for bloating, eductyl (potassium tartrate acid) for constipation, ondansetron for vomiting, platelet transfusion for platelet count decreased, and calciparine (heparin calcium) for thromboembolic event.The patient died on (b)(6) 2018.Follow up information received on 02-feb-2018: the investigator specified the reason for patient's encephalopathy and death as hepatocellular insufficiency.Further laboratory test result values taken on (b)(6) 2017 (before hospitalization) and (b)(6) 2018 were provided.Details are outlined in the structured information.Follow up information received on 01-mar-2018: the investigator clarified that he did not consider the seriousness criterion 'fatal' (results in death) applicable for the event term general state alteration.Furthermore, the cause of the death 'hepatobiliary insufficiency' was confirmed as separate sae and the seriousness criterion provided as 'fatal' (results in death).Follow up information received on 15-mar-2018 and 19-mar-2018: the investigator considered the hepatocellular insufficiency as probably related to sir-spheres microspheres (mapping and implantation) and possibly related to cisplatin since the insufficiency occurred after transarterial radioembolization (tare) and chemotherapy without underlying liver disease.Please note: after internal review, it was noted that "hepatobiliary" insufficiency was erroneously written in the case narrative and reporter's comment.With resolved query from (b)(6) 2018, it was confirmed by the investigator that the assessment was provided for "hepatocellular" insufficiency.Therefore, "hepatobiliary" should read as "hepatocellular".Follow-up information received on 21-mar-2018: the investigator confirmed that no complications have occurred during sir-spheres microspheres mapping and implant procedure.Reporter's comment: the investigator did not provide a causality assessment regarding the serious adverse event and chemotherapy agents.With follow-up information received on 24-jan-2018, the investigator assessed the sae of general state alteration as possibly related to sir-spheres microspheres (medical device), cisplatin and gemcitabine and as not related to sir-spheres microspheres (mapping and implant procedure).The saes of blood bilirubin increased, platelet count decreased, and encephalopathy were assessed as possibly related to sir-spheres microspheres (medical device) and as not related to sir-spheres microspheres (mapping and implant procedure), cisplatin and gemcitabine.With follow-up information received on 01-mar-2018, the investigator assessed the event hepatobiliary insufficiency as probable/likely related to sir-spheres microspheres device, sir-spheres microspheres mapping procedure, and sir-spheres microspheres implant procedure, and possibly related to cisplatin and gemcitabine.Please note, this report has also been submitted as an ide report (b)(4).
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Event Description
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This report combines information received between 22-dec-2017 and 01-mar-2018.This is the initial medical device report submitted to the fda.With follow-up information received on 24-jan-2018 the case classified as unanticipated serious adverse device effect report as the investigator provided information on sir-spheres microspheres treatment and included a causality assessment.A serious adverse event report ((b)(4)) was received on 22-dec-2017 from an investigator in france regarding a female patient, (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 (b)(6).The reported event term was general state alteration.The patient's medical history was significant for unresectable intrahepatic cholangiocarcinoma.Concomitant medication was not reported.The patient received a combined treatment modality (sir-spheres microspheres + cis-gem chemotherapy).The event occurred after chemotherapy cycle 4 started on (b)(6) 2017.The second administration was performed on (b)(6) 2017.On (b)(6) 2017, the patient presented with general state alteration, lower limb obliteration "majoration", erythema on the left lower limb, painful, without fever.Acute kidney failure and increasing biological signs of hepatocellular insufficiency were noted.The event was severe.The patient was hospitalised on (b)(6) 2017.The patient was not withdrawn from the study due to this event.At the time of the report, the event was ongoing and the patient's outcome was reported as "not recovered".Follow up information was received on 24-jan-2018.The investigator provided the following information regarding treatment with sir-spheres microspheres: mapping procedure was performed on (b)(6) 2017.Implantation of sir-spheres microspheres (1.479 gbq, batch no.Lh415v03) was performed on (b)(6) 2017 via right branch.Further medical history included hypertension, hypercholesterolemia, hypothyroidism, valvular leakage, edema limbs, and diabetes.Concomitant medication included: sotalex (sotalol hydrochloride), 160 mg daily, oral, from 2002 to (b)(6) 2018, for valvular leakage simvastatine, 20 mg daily, oral, from 2002 to (b)(6) 2018, for hypercholesterolemia levothyrox (levothyroxine), 75 mg daily, oral, from 2007 to (b)(6) 2018, for hypothyroidism indapamide, 1.5 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for hypertension amlodipine, 5 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for hypertension metformine, 2100 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for diabetes furosemide, 40 mg daily, oral, from (b)(6) 2017 to (b)(6) 2018, for edema limbs after hospitalisation due to general state alteration on (b)(6) 2017, the patient experienced further adverse events during hospitalisation: dyspnea, erythema, mucositis oral, erysipelas, ascites, oral hemorrhage, anemia, abdominal pain, constipation, vomiting, creatinine increased, aspartate aminotransferase (asat) increased, alanine aminotransferase (alat) increased, gamma-glutamyltransferase (ggt) increased, alkaline phosphatase (pal) increased, bloating and thromboembolic event.On (b)(6) 2017, the patient experienced the serious adverse events of blood bilirubin increased (severity: life-threatening) and encephalopathy (severity: severe).On (b)(6) 2017, the patient experienced the serious adverse event of platelet count decreased (severity: life-threatening).Relevant laboratory test results are provided as structured information.The patient was treated with albumin and ceftriaxone for ascites, sodium bicarbonate and fungizone (amphotericin b) for mucositis oral, duphalac (lactulose) and rifaximin for encephalopathy, amoxicillin for erysipelas, paracetamol, phloroglucinol, and oxycodone for abdominal pain, trimebutine for bloating, eductyl (potassium tartrate acid) for constipation, ondansetron for vomiting, platelet transfusion for platelet count decreased, and calciparine (heparin calcium) for thromboembolic event.The patient died on (b)(6) 2018.Follow up information received on 02-feb-2018: the investigator specified the reason for patient's encephalopathy and death as hepatocellular insufficiency.Further laboratory test result values taken on (b)(6) 2017 (before hospitalization) and (b)(6) 2018 were provided.Details are outlined in the structured information.Follow up information received on 01-mar-2018: the investigator clarified that he did not consider the seriousness criterion 'fatal' (results in death) applicable for the event term general state alteration.Furthermore, the cause of the death 'hepatobiliary insufficiency' was confirmed as separate sae and the seriousness criterion provided as 'fatal' (results in death).Follow up information received on 15-mar-2018 and 19-mar-2018: the investigator considered the hepatocellular insufficiency as probably related to sir-spheres microspheres (mapping and implantation) and possibly related to cisplatin since the insufficiency occurred after transarterial radioembolization (tare) and chemotherapy without underlying liver disease.Please note: after internal review, it was noted that "hepatobiliary" insufficiency was erroneously written in the case narrative and reporter's comment.With resolved query from (b)(6) 2018, it was confirmed by the investigator that the assessment was provided for "hepatocellular" insufficiency.Therefore, "hepatobiliary" should read as "hepatocellular".Reporter's comment: the investigator did not provide a causality assessment regarding the serious adverse event and chemotherapy agents.With follow-up information received on 24-jan-2018, the investigator assessed the sae of general state alteration as possibly related to sir-spheres microspheres (medical device), cisplatin and gemcitabine and as not related to sir-spheres microspheres (mapping and implant procedure).The saes of blood bilirubin increased, platelet count decreased, and encephalopathy were assessed as possibly related to sir-spheres microspheres (medical device) and as not related to sir-spheres microspheres (mapping and implant procedure), cisplatin and gemcitabine.With follow-up information received on 01-mar-2018, the investigator assessed the event hepatobiliary insufficiency as probable/likely related to sir-spheres microspheres device, sir-spheres microspheres mapping procedure, and sir-spheres microspheres implant procedure, and possibly related to cisplatin and gemcitabine.(b)(4).
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Manufacturer Narrative
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Serious adverse event of general physical health deterioration led to hospitalization of a (b)(6) female patient 28 days after the second administration of chemotherapy within cycle 4.Treatment with sir-spheres microspheres was not reported.The temporal relationship is considered plausible for cisplatin and gemcitabine.General physical health deterioration is unexpected for cisplatin and gemcitabine.The patient experienced multiple symptoms.Acute kidney failure is a known side effect of gemcitabine and cisplatin and it is known that gemcitabine might act hepatotoxically.Furthermore, both chemotherapeutics may cause asthenia promoting alteration of general state.However, the patient's underlying disease of unresectable intrahepatic cholangiocarcinoma also provides a plausible explanation for increasing signs of hepatocellular insufficiency contributing to deterioration of health.The investigator's assessment was not provided.Considering the plausible temporal course and the known safety profile of gemcitabine and cisplatin the sponsor assesses a contributing role of both chemotherapeutics to general physical health alteration as possible.With follow-up information received on 24-jan-2018 it was clarified that the patient received sir-spheres microspheres and the events blood bilirubin increased, platelet count decreased and encephalopathy were added.The adverse events of general physical health deterioration, blood bilirubin increased, platelet count increased and encephalopathy were classified as serious since they required hospitalization of an (b)(6) female patient about 17 weeks after mapping procedure, 16 weeks after sir-spheres microspheres implantation and 4 weeks after the second administration of chemotherapy within cycle 4.General physical health deterioration is unexpected for sir-spheres microspheres, mapping and implantation procedure and chemotherapy.Blood bilirubin increased and platelet count decreased are expected for cisplatin and gemcitabine and unexpected for sir-spheres microspheres and related procedures.Encephalopathy is unexpected for all imps and procedures.The temporal relationship is implausible for sir-spheres microspheres, mapping and implant procedure but plausible for cisplatin and gemcitabine regarding all events.Noteworthy, the patient also suffered from further issues, including ascites, elevation of liver values and creatinine, which might be indicative for progression of her malignant disease.Thus, her underlying cholangiocarcinoma may have promoted bilirubin increase and also encephalopathy considering a possible hepatic genesis (hepatic encephalopathy), however, etiology of encephalopathy was not provided.Furthermore, hepatic encephalopathy is a known side effect of the patient's concomitant medication of indapamide and furosemide.In addition, chemotherapy is known to cause bilirubin increase and platelet count decrease, which provides a likely alternative explanation for these events.Overall, all these events as well as the underlying malignant disease might have contributed to the patient's general physical health deterioration for which the outcome was provided as fatal.The investigator assessed general physical health deterioration as possibly related to sir-spheres microspheres, cisplatin and gemcitabine and as not related to mapping and implant procedure.Blood bilirubin increased, platelet count decreased, and encephalopathy were assessed as possibly related to sir-spheres microspheres and as not related to procedures and chemotherapy.Considering the implausible temporal course and the plausible alternative explanation, the events general physical health deterioration, blood bilirubin increased, platelet count decreased and encephalopathy are assessed as unlikely related to sir-spheres microspheres and not related to mapping and implant procedure.Based on known safety profile and plausible temporal course blood bilirubin increased and platelet count decreased are assessed as possibly related to cisplatin and gemcitabine, while encephalopathy is assessed as unlikely related to chemotherapy.The initial causality assessment for general physical health deterioration remains unchanged as possibly related to chemotherapy.With follow-up information received on 02-feb-2018 it was clarified that the patient died due to hepatocellular insufficiency, therefore the event hepatic insufficiency was added.In addition, the etiology for encephalopathy was provided as hepatocellular insufficiency.Thus, the event encephalopathy was amended to hepatic encephalopathy.The event hepatic insufficiency is expected for sir-spheres microspheres and gemcitabine and unexpected for cisplatin and mapping and implant procedure.The event hepatic encephalopathy is expected for sir-spheres microspheres and unexpected for mapping and implant procedure, cisplatin and gemcitabine, although hepatotoxicity is a known side effect of gemcitabine.No exact onset date for hepatocellular insufficiency was provided, however death due to the event occurred 4.5 months after mapping and implantation procedure and two months after latest chemotherapy administration.Considering latency time and cumulative effects, the temporal relationship of both hepatic insufficiency and hepatic encephalopathy is considered plausible for sir-spheres microspheres and for chemotherapy and implausible for sir-spheres microspheres procedures.The patient's underlying malignant disease provides a plausible explanation for both hepatic encephalopathy and insufficiency and the concomitant medication including indapamide and furosemide may have also promoted the events.The sponsor assessed the causality for hepatic encephalopathy and hepatic insufficiency as possibly related to sir-spheres microspheres and gemcitabine, unlikely related to cisplatin and not related to mapping and implant procedure.The sponsor's causality assessment for all other events remains unchanged.The investigator did not provide a causality assessment for hepatic insufficiency and the investigator's causality for all other events remains unchanged.With follow-up information received on 01-mar-2018 the investigator provided his causality assessment for the event hepatic insufficiency: probably related to sir-spheres microspheres, sir-spheres mapping and implant procedure and possibly related to gemcitabine and cisplatin.The sponsor's assessment remains unchanged, considering the temporal course and contributing factors: possibly related to sir-spheres microspheres and gemcitabine, unlikely related to cisplatin and not related to mapping and implant procedure.The causality assessment for all other events remains unchanged.With follow-up information received on 15-mar-2018 the investigator clarified that hepatic insufficiency was considered as probably related to sir-spheres microspheres mapping and implantation and possibly related to cisplatin since the insufficiency occurred after transarterial radioembolization and chemotherapy without underlying liver disease.No further details, such as information on possible complications during the procedures was provided and considering the temporal course and underlying intrahepatic cholangiocarcinoma, the sponsor's causality assessment for hepatic insufficiency remains unchanged: possibly related to sir-spheres microspheres and gemcitabine, unlikely related to cisplatin and not related to mapping and implant procedure.
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