| Lot Number NI403V09 |
| Device Problem
Adverse Event Without Identified Device or Use Problem (2993)
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| Patient Problems
Encephalopathy (1833); Confusion/ Disorientation (2553)
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| Event Date 01/30/2020 |
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Event Type
Death
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Manufacturer Narrative
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The adverse events of radiation-induced liver disease (reild) and encephalopathy were classified as serious since the (b)(6)-year old male patient was hospitalized about 2 months after start of the 3rd chemotherapy cycle and nearly 5 months after implantation of sir-spheres microspheres.Reild is expected for sir-spheres microspheres and unexpected for related procedures and chemotherapy.Encephalopathy is unexpected for sir-spheres microspheres (only hepatic encephalopathy expected), related procedures and chemotherapy.The temporal relationship is implausible regarding the procedures and plausible for chemotherapy and sir-spheres microspheres considering latency effects and the previous hospitalization.Usually reild occurs 4-8 weeks after sirt and of note, general status deterioration, which was later considered to be caused by reild, led to hospitalization about 2 months after implantation procedure (see linked case (b)(4)).The concurrently reported cognitive impairment may have been an early symptom of the event encephalopathy, however according to the linked case the event had resolved about 3 weeks after onset and therefore it remains unclear whether this was a symptom or an independent episode.The test results provided were consistent with what is typically seen in reild since the patient showed elevation of bilirubin above 3mg/dl as well as increased alp, increased ggt and hepatic ultrasound did not show biliary duct expansion.Of note, no further information on clinical picture and details on further diagnostic work-up were available.An eeg revealed that the patient suffered from metabolic encephalopathy.The patient's advanced age is associated with an increased risk and hepatic insufficiency and imbalances such as hyperglycaemia have been associated with the development of the metabolic encephalopathy (berisavac et al., 2017).Of note, metabolic encephalopathy is unexpected for sir-spheres microspheres, whereas hepatic encephalopathy is expected and may be the more specific diagnosis here, although this was not confirmed and no further details were available.The investigator assessed the events as probably related to sir-spheres microspheres, unlikely related to procedures and not related to chemotherapy.Based on the information available and as the encephalopathy occurred concurrently with reild, the sponsor concurs and assesses the events as related to sir-spheres microspheres and not related to procedures and chemotherapy.
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Event Description
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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 31-jan-2020: the reported event terms were radioembolization induced liver disease (reild) and encephalopathy.At the time of the event onset the patient was (b)(6)-year-old.This case is linked to case number (b)(4) (sae terms: general physical health deterioration and cognitive disorder).The patient's medical history was significant for unresectable intrahepatic cholangiocarcinoma, cardiac arrhythmia, diagnosed on (b)(6) 2004, and high blood pressure, all ongoing, as well as ascites, status unknown.Concomitant medication included methylprednisolone tablets, 20 mg per day, orally, from (b)(6) 2020 for reild, aldactone tablets (spironolactone), 50 mg per day, orally, since (b)(6) 2020 for ascites, lasilix tablets (furosemide), at an unknown dose, orally, from (b)(6) 2020 for ascites and delursan tablets (ursodeoxycholic acid), 250 mg per day, orally, since (b)(6) 2020 for reild.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 (1.87 gbq, batch no.Ni403v09) was performed on (b)(6) 2019 via right and left hepatic arteries.The events occurred during chemotherapy cycle 03 started on (b)(6) 2019.The second administration was not yet performed.On (b)(6) 2020, the patient was hospitalized due to an important general status deterioration (oms4) and worsening confusion without waking up and loss of autonomy.The event of reild was life-threatening, the encephalopathy was severe.A hepatic ultrasound was done but did not show a biliary duct expansion.An eeg was performed, revealing a metabolic encephalopathy.Further relevant laboratory/diagnostic tests included total bilirubin = 63 um (reference range: 1-17 um), ggt = 848 ui/l (reference range: 8-61 ui/l), apl = 298 ui/l (reference range: 40-130 ui/l) and glycemia = 3.8 g/l (reference range: 0.65-1.15 g/l).The patient was treated with an increase of methylprednisolone to 1 mg/kg/day.At the time of the report, the events were ongoing.Reporter's comments: the investigator assessed the events as unlikely related to the sir-spheres microspheres mapping and implant procedure, as probably related to sir-spheres microspheres (medical device) and as not related to cisplatin and gemcitabine.
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Event Description
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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 31-jan-2020: the reported event terms were radioembolization induced liver disease (reild) and encephalopathy.At the time of the event onset the patient was 78-year-old.This case is linked to case number (b)(4) (sae terms: general physical health deterioration and cognitive disorder).The patient's medical history was significant for unresectable intrahepatic cholangiocarcinoma, cardiac arrhythmia, diagnosed on (b)(6) 2004, and high blood pressure, all ongoing, as well as ascites, status unknown.Concomitant medication included methylprednisolone tablets, 20 mg per day, orally, from (b)(6) 2020 for reild, aldactone tablets (spironolactone), 50 mg per day, orally, since (b)(6) 2020 for ascites, lasilix tablets (furosemide), at an unknown dose, orally, from (b)(6) 2020 for ascites and delursan tablets (ursodeoxycholic acid), 250 mg per day, orally, since (b)(6) 2020 for reild.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 (1.87 gbq, batch no.Ni403v09) was performed on (b)(6) 2019 via right and left hepatic arteries.The events occurred during chemotherapy cycle 03 started on (b)(6) 2019.The second administration was not yet performed.On (b)(6) 2020, the patient was hospitalized due to an important general status deterioration (oms4) and worsening confusion without waking up and loss of autonomy.The event of reild was life-threatening, the encephalopathy was severe.A hepatic ultrasound was done but did not show a biliary duct expansion.An eeg was performed, revealing a metabolic encephalopathy.Further relevant laboratory/diagnostic tests included total bilirubin = 63 m (reference range: 1-17 m), ggt = 848 ui/l (reference range: 8-61 ui/l), apl = 298 ui/l (reference range: 40-130 ui/l) and glycemia = 3.8 g/l (reference range: 0.65-1.15 g/l).The patient was treated with an increase of methylprednisolone to 1 mg/kg/day.At the time of the report, the events were ongoing.Follow-up information was received on 09-mar-2020: the encephalopathy was reported to be a hepatic encephalopathy.Further relevant examination results were provided, see structured information.Last chemotherapy administration prior to the events was on (b)(6) 2019.The patient died on (b)(6) 2020.It was further clarified that the reported events of linked case (b)(4) were considered as symptoms of the events of reild and hepatic encephalopathy.On (b)(6) 2019, the patient had previously been hospitalized for general status deterioration and neurological disorders.Both events were severe.At that time concomitant medication included oxycontin lp (oxycodone hydrochloride), 15 times 2mg daily, per oral from (b)(6) 2019, oxycodone, 0.4 mg/h daily, intravenously, from (b)(6) 2019 and oxycodone, 10 times 2 mg and 1.6 times 5 mg per day, per oral since (b)(6) 2019, all against pain.The concomitant medication was prescribed for abdominal pain due to underlying disease, and buttock pain due to falls.An eeg, performed on (b)(6) 2019, showed a "globally slowed electrogenesis consistent with metabolic or toxic encephalopathy".Results of a lumbar puncture were negative.For laboratory values please see structured information.Neurological disorders were explored but no response could be found to explain the patient's confusion.The patient was treated with methylprednisolone with success.The patient was discharged from hospital on (b)(6) 2019 with no more neurological disorder and general status improvement.With further information received on (b)(6) 2019 and (b)(6) 2020 the neurological disorder was specified as cognitive disorder, exact diagnosis unknown, and space-time disorientation during the night, but improved with cortico-therapy.General status deterioration manifested as the patient being very tired, confused and disoriented.It was thought to possibly be due to chemotherapy cycles and was improved until discharge.With information received on (b)(6) 2020 the final cause for general status deterioration was provided as not related to chemotherapy but as probably related to a beginning radioembolization induced liver disease.Reporter's comments: the investigator assessed the events as unlikely related to the sir-spheres microspheres mapping and implant procedure, as probably related to sir-spheres microspheres (medical device) and as not related to cisplatin and gemcitabine.(b)(4).
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Manufacturer Narrative
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The adverse events of radiation-induced liver disease (reild) and encephalopathy were classified as serious since the 78-year old male patient was hospitalized about 2 months after start of the 3rd chemotherapy cycle and nearly 5 months after implantation of sir-spheres microspheres.Reild is expected for sir-spheres microspheres and unexpected for related procedures and chemotherapy.Encephalopathy is unexpected for sir-spheres microspheres (only hepatic encephalopathy expected), related procedures and chemotherapy.The temporal relationship is implausible regarding the procedures and plausible for chemotherapy and sir-spheres microspheres considering latency effects and the previous hospitalization.Usually reild occurs 4-8 weeks after sirt and of note, general status deterioration, which was later considered to be caused by reild, led to hospitalization about 2 months after implantation procedure (see linked case (b)(4)).The concurrently reported cognitive impairment may have been an early symptom of the event encephalopathy, however according to the linked case the event had resolved about 3 weeks after onset and therefore it remains unclear whether this was a symptom or an independent episode.The test results provided were consistent with what is typically seen in reild since the patient showed elevation of bilirubin above 3mg/dl as well as increased alp, increased ggt and hepatic ultrasound did not show biliary duct expansion.Of note, no further information on clinical picture and details on further diagnostic work-up were available.An eeg revealed that the patient suffered from metabolic encephalopathy.The patient's advanced age is associated with an increased risk and hepatic insufficiency and imbalances such as hyperglycaemia have been associated with the development of the metabolic encephalopathy (berisavac et al., 2017).Of note, metabolic encephalopathy is unexpected for sir-spheres microspheres, whereas hepatic encephalopathy is expected and may be the more specific diagnosis here, although this was not confirmed and no further details were available.The investigator assessed the events as probably related to sir-spheres microspheres, unlikely related to procedures and not related to chemotherapy.Based on the information available and as the encephalopathy occurred concurrently with reild, the sponsor concurs and assesses the events as related to sir-spheres microspheres and not related to procedures and chemotherapy.With follow-up information received on 09-mar-2020 the event encephalopathy was amended to hepatic encephalopathy and the seriousness criterion the patient died was added.Hepatic encephalopathy (including fatal outcome) is expected for sir-spheres microspheres and unexpected for procedures and chemotherapy.In addition, it was clarified that the previously reported events of general physical health deterioration and cognitive disorder with an onset about 2.5 months prior to the recent hospitalization were considered as symptoms of reild and hepatic encephalopathy.During this previous episode the patient had been hospitalized for 3 weeks and as his symptoms resolved under therapy, he had been discharged home.Nearly 2 months later the patient was readmitted to hospital and diagnosed with the reported events and died about 3 weeks after this second hospital admission.The sponsor's assessment remains unchanged for both events as possibly related to sir-spheres microspheres and not related to procedures and chemotherapy.
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Search Alerts/Recalls
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