MAUDE Adverse Event Report: SIRTEX TECHNOLOGY PTY LTD / SIRTEX MEDICAL LIMITED SIR-SPHERES® Y-90 RESIN MICROSPHERES

Lot Number MA410V02

Device Problem Adverse Event Without Identified Device or Use Problem (2993)

Patient Problem Diarrhea (1811)

Event Date 04/11/2018

Event Type  Injury  

Manufacturer Narrative

The adverse event of diarrhea was classified as serious since it required hospitalization of a (b)(6) year old male patient at an unknown time during therapy with sir-spheres microspheres and nivolumab.Diarrhea is expected for nivolumab and sir-spheres microspheres and unexpected for sir-spheres microspheres mapping and implant procedures.In absence of treatment dates, the temporal relationship is not assessable for sir-spheres microspheres, mapping and implant procedure and nivolumab.Noteworthy, the patient's underlying hepatocellular carcinoma can present with diarrhea (atwa et el-etreby 2015).The investigator assessed the event as possibly related to nivolumab and did not provide a causality assessment for sir-spheres microspheres, mapping and implant procedure on the initial sae report form.Of note, email correspondence with the responsible cro revealed that the investigator assessed the event as not related to sirt according to the crf.However, the paucity of information available, lacking especially information if and when sir-spheres microspheres were implanted, precludes a comprehensive evaluation.Thus, the causality is considered not assessable for sir-spheres microspheres and related procedures by the sponsor.The causality for nivolumab is assessed as possible, considering the known safety profile of nivolumab and following the investigator's statement on the sae report form.With follow-up information received on 26-apr-2018 and 30-apr-2018 information of treatment dates with nivolumab as well as sir-spheres microspheres were provided.For nivolumab the temporal relationship is plausible as the event occurred under ongoing therapy and for sir-spheres microspheres and related procedures the temporal course is implausible as diarrhea occurred nearly eleven weeks after start date of sir-spheres microspheres.In addition, the investigator provided the causality assessment for sir-spheres microspheres, mapping and implant procedure, assessing the event as possibly related to sir-spheres microspheres and related procedures.However, considering the implausible temporal course, the sponsor assesses the event as not related for sir-spheres microspheres, mapping and implant procedures.For nivolumab the sponsor's causality assessment remains unchanged as possibly related.

Event Description

This report combines information received between 16-apr-2018 and 30-apr-2018.This is the initial medical device report submitted to the fda.A serious adverse event report, (case number (b)(4)) was received from an investigator in spain regarding a male patient (patient no.(b)(6)) enrolled in "(b)(6) study of the safety and antitumoral efficacy of nivolumab after selective internal radiation therapy (sirt) using sir-spheres for the treatment of patients with hepatocellular carcinoma that are candidates for locoregional therapies (nasir-hcc)", study code (b)(4).Initial report was received on 16-apr-2018: the reported event term was diarrhea.At the time of the event onset, the patient was (b)(6) year-old.This patient experienced the following sae in the past: creatinine increased ((b)(4)).The patient's medical history was significant for hepatocellular carcinoma.The patient received a combined treatment modality of sir-spheres microspheres + nivolumab chemotherapy.No information regarding sir-spheres microspheres and nivolumab treatment were provided.At the time of the event, the patient did not receive any concomitant medication.On (b)(6) 2018, the patient experienced diarrhea and was hospitalised.The event was severe.For relevant diagnostic results, see structured information.The patient was treated with urbason (methylprednisolone) 60 mg, every 24 hours, intravenous starting 13-apr-2018, ondansetron 5-10 mg, every 24 hours, intravenous starting 11-apr-2018, and ideos (calcium and vitamin d) one tablet every 12 hours, oral starting (b)(6) 2018.At the time of the report, the event was ongoing.Follow-up information was received on 26-apr-2018 and 30-apr-2018.Treatment with nivolumab (240 mg, every 15 days, batch number aak4491) was started on (b)(6) 2018 and was ongoing.Sir-spheres microspheres (batch number ma410v02) start date was provided as (b)(6) 2018.Dechallenge and rechallenge for sir-spheres microspheres were reported as "not applicable".Sir-spheres microspheres have not been readministered.Reporter's comment: the investigator assessed the event as possibly related to nivolumab.No causality assessment for sir-spheres microspheres (mapping procedure), sir-spheres microspheres (implant procedure) and sir-spheres microspheres (medical device) was provided.With follow-up information received on 26-apr-2018, the investigator assessed the event as possibly related to sir-spheres microspheres (mapping procedure), sir-spheres microspheres (implant procedure) and sir-spheres microspheres (medical device).

Event Description

This report combines information received between 16-apr-2018 and 30-apr-2018.This is the initial medical device report submitted to the fda.A serious adverse event report, (case number (b)(4) was received from an investigator in spain regarding a male patient (patient no.(b)(6)) enrolled in "a multicenter, open-label, single-arm study of the safety and antitumoral efficacy of nivolumab after selective internal radiation therapy (sirt) using sir-spheres for the treatment of patients with hepatocellular carcinoma that are candidates for locoregional therapies (nasir-hcc)", study code (b)(6) initial report was received on 16-apr-2018: the reported event term was diarrhea.At the time of the event onset the patient was 7(b)(6).This patient experienced the following sae in the past: creatinine increased ((b)(4)).The patient's medical history was significant for hepatocellular carcinoma.The patient received a combined treatment modality of sir-spheres microspheres + nivolumab chemotherapy.No information regarding sir-spheres microspheres and nivolumab treatment were provided.At the time of the event, the patient did not receive any concomitant medication.On (b)(6) 2018, the patient experienced diarrhea and was hospitalised.The event was severe.For relevant diagnostic results, see structured information.The patient was treated with urbason (methylprednisolone) 60 mg, every 24 hours, intravenous starting (b)(6) 2018, ondansetron 5-10 mg, every 24 hours, intravenous starting (b)(6) 2018, and ideos (calcium and vitamin d) one tablet every 12 hours, oral starting (b)(6) 2018.At the time of the report, the event was ongoing.Follow-up information was received on 26-apr-2018 and 30-apr-2018.Treatment with nivolumab (240 mg, every 15 days, batch number aak4491) was started on (b)(6) 2018 and was ongoing.Sir-spheres microspheres (batch number ma410v02) start date was provided as (b)(6) 2018.Dechallenge and rechallenge for sir-spheres microspheres were reported as "not applicable".Sir-spheres microspheres have not been readministered.Follow-up information was received on 18-jun-2018.The reported event term was changed to "diarrhea immunorelated".The end date was provided (b)(6) 2018.However, the outcome was reported as ongoing.Reporter's comment: the investigator assessed the event as possibly related to nivolumab.No causality assessment for sir-spheres microspheres (mapping procedure), sir-spheres microspheres (implant procedure) and sir-spheres microspheres (medical device) was provided.With follow-up information received on 26-apr-2018, the investigator assessed the event as possibly related to sir-spheres microspheres (mapping procedure), sir-spheres microspheres (implant procedure) and sir-spheres microspheres (medical device).

Manufacturer Narrative

The adverse event of diarrhea was classified as serious since it required hospitalization of a (b)(6) male patient at an unknown time during therapy with sir-spheres microspheres and nivolumab.Diarrhea is expected for nivolumab and sir-spheres microspheres and unexpected for sir-spheres microspheres mapping and implant procedures.In absence of treatment dates, the temporal relationship is not assessable for sir-spheres microspheres, mapping and implant procedure and nivolumab.Noteworthy the patient's underlying hepatocellular carcinoma can present with diarrhea (atwa et el-etreby 2015).The investigator assessed the event as possibly related to nivolumab and did not provide a causality assessment for sir-spheres microspheres, mapping and implant procedure on the initial sae report form.Of note, email correspondence with the responsible cro revealed that the investigator assessed the event as not related to sirt according to the crf.However, the paucity of information available, lacking especially information if and when sir-spheres microspheres were implanted, precludes a comprehensive evaluation.Thus, the causality is considered not assessable for sir-spheres microspheres and related procedures by the sponsor.The causality for nivolumab is assessed as possible, considering the known safety profile of nivolumab and following the investigator's statement on the sae report form.With follow-up information received on 26-apr-2018 and 30-apr-2018 information of treatment dates with nivolumab as well as sir-spheres microspheres were provided.For nivolumab the temporal relationship is plausible as the event occurred under ongoing therapy and for sir-spheres microspheres and related procedures the temporal course is implausible as diarrhea occurred nearly eleven weeks after start date of sir-spheres microspheres.In addition, the investigator provided the causality assessment for sir-spheres microspheres, mapping and implant procedure, assessing the event as possibly related to sir-spheres microspheres and related procedures.However, considering the implausible temporal course, the sponsor assesses the event as not related for sir-spheres microspheres, mapping and implant procedures.For nivolumab the sponsor's causality assessment remains unchanged as possibly related.With follow-up information received on 18-jun-2018 the event immune-mediated adverse reaction was added since the verbatim was amended from diarrhoea to diarrhoea immunorelated.Although immune-mediated adverse event per se is not listed according to the ib of nivolumab, in this context the event is considered expected since the verbatim characterizes diarrhoea and refers to the immune-mediating effect of nivolumab, which is well-known.The causality assessment remains unchanged as possibly related to nivolumab and not related for sir-spheres microspheres, mapping and implant procedures.

Event Description

With follow-up information received on 13-jul-2018, the investigator changed his causality assessment to not related to sir-spheres microspheres.The case is no longer considered reportable as emdr.A serious adverse event report, (case number (b)(4)) was received from an investigator in spain regarding a male patient (patient no.(b)(6)) enrolled in "a multicenter, open-label, single-arm study of the safety and antitumoral efficacy of nivolumab after selective internal radiation therapy (sirt) using sir-spheres for the treatment of patients with hepatocellular carcinoma that are candidates for locoregional therapies (nasir-hcc)", study code ca209-992.Initial report was received on 16-apr-2018: the reported event term was diarrhea.At the time of the event onset the patient was 75-year-old.This patient experienced the following sae in the past: creatinine increased (b)(4).The patient's medical history was significant for hepatocellular carcinoma.The patient received a combined treatment modality of sir-spheres microspheres + nivolumab chemotherapy.No information regarding sir-spheres microspheres and nivolumab treatment were provided.At the time of the event, the patient did not receive any concomitant medication.On (b)(6) 2018, the patient experienced diarrhea and was hospitalised.The event was severe.For relevant diagnostic results, see structured information.The patient was treated with urbason (methylprednisolone) 60 mg, every 24 hours, intravenous starting (b)(6) 2018, ondansetron 5-10 mg, every 24 hours, intravenous starting (b)(6) 2018, and ideos (calcium and vitamin d) one tablet every 12 hours, oral starting (b)(6) 2018.At the time of the report, the event was ongoing.Follow-up information was received on 26-apr-2018 and 30-apr-2018.Treatment with nivolumab (240 mg, every 15 days, batch number aak4491) was started on (b)(6) 2018 and was ongoing.Sir-spheres microspheres (batch number ma410v02) start date was provided as (b)(6) 2018.Dechallenge and rechallenge for sir-spheres microspheres were reported as "not applicable".Sir-spheres microspheres have not been readministered.Follow-up information was received on 18-jun-2018.The reported event term was changed to "diarrhea immunorelated".The end date was provided (b)(6) 2018.However, the outcome was reported as ongoing.Follow-up information was received on 13-jul-2018.The date of sir-spheres microspheres mapping procedure was provided as (b)(6) 2018.The last administration of nivolumab prior to the event was on (b)(6) 2018.Hospitalization dates were provided as (b)(6) 2018 to (b)(6) 2018.The outcome was reported as "recovered without sequelae".Histopathological results were compatible with lymphocytic colitis.Further medical history included arterial hypertension, dyslipidemia, hyperuricemia, colonic polyps (since 2010) and anemia iron deficiency (since 2017), all ongoing.Concomitant medication was provided as acentensil plus (enalapril/hydrochlorothiazide) 20/12.5 mg, oral and capoten (captopril) 25 mg daily oral, both for arterial hypertension and ongoing.Additional information on treatment medication included methylprednisolone 60 mg, oral from (b)(6) 2018 and 40 mg from (b)(6) 2018 and ongoing, albumin, intravenous from (b)(6) 2018, metronidazole and ciprofloxacin, both intravenous from (b)(6) 2018; bicarbonate, intravenous from (b)(6) 2018, furosemide, intravenous from (b)(6) 2018 and ongoing, ceftriaxone from (b)(6) 2018, septrim forte (cotrimoxazole), oral from (b)(6) 2018, and omeprazole, oral start date (b)(6) 2018 and ongoing.In addition, ferinject (iron) was started on (b)(6) 2018 for anemia, levofloxacin 500 mg, oral was given from (b)(6) 2018 for pneumonia, augmentine (amoxicillin/clavulanic acid) 875/125 mg, one dose and casen biotic (lactic acid bacterium) one tablet, oral were administered from (b)(6) 2018 to (b)(6) 2018 for escherichia coli urinary tract infection.Reporter's comment: the investigator assessed the event as possibly related to nivolumab.No causality assessment for sir-spheres microspheres (mapping procedure), sir-spheres microspheres (implant procedure) and sir-spheres microspheres (medical device) was provided.With follow-up information received on 26-apr-2018, the investigator assessed the event as possibly related to sir-spheres microspheres (mapping procedure), sir-spheres microspheres (implant procedure) and sir-spheres microspheres (medical device).With follow-up information received on 13-jul-2018, the investigator assessed the event as not related to sir-spheres microspheres (mapping procedure), sir-spheres microspheres (implant procedure) and sir-spheres microspheres (medical device) and unlikely related to nivolumab.

Manufacturer Narrative

The adverse event of diarrhea was classified as serious since it required hospitalization of a 75-year old male patient at an unknown time during therapy with sir-spheres microspheres and nivolumab.Diarrhea is expected for nivolumab and sir-spheres microspheres and unexpected for sir-spheres microspheres mapping and implant procedures.In absence of treatment dates, the temporal relationship is not assessable for sir-spheres microspheres, mapping and implant procedure and nivolumab.Noteworthy the patient's underlying hepatocellular carcinoma can present with diarrhea (atwa et el-etreby 2015).The investigator assessed the event as possibly related to nivolumab and did not provide a causality assessment for sir-spheres microspheres, mapping and implant procedure on the initial sae report form.Of note, email correspondence with the responsible cro revealed that the investigator assessed the event as not related to sirt according to the crf.However, the paucity of information available, lacking especially information if and when sir-spheres microspheres were implanted, precludes a comprehensive evaluation.Thus, the causality is considered not assessable for sir-spheres microspheres and related procedures by the sponsor.The causality for nivolumab is assessed as possible, considering the known safety profile of nivolumab and following the investigator's statement on the sae report form.With follow-up information received on 26-apr-2018 and 30-apr-2018 information of treatment dates with nivolumab as well as sir-spheres microspheres were provided.For nivolumab the temporal relationship is plausible as the event occurred under ongoing therapy and for sir-spheres microspheres and related procedures the temporal course is implausible as diarrhea occurred nearly eleven weeks after start date of sir-spheres microspheres.In addition, the investigator provided the causality assessment for sir-spheres microspheres, mapping and implant procedure, assessing the event as possibly related to sir-spheres microspheres and related procedures.However, considering the implausible temporal course, the sponsor assesses the event as not related for sir-spheres microspheres, mapping and implant procedures.For nivolumab the sponsor's causality assessment remains unchanged as possibly related.With follow-up information received on 18-jun-2018 the event immune-mediated adverse reaction was added since the verbatim was amended from diarrhoea to diarrhoea immunorelated.Although immune-mediated adverse event per se is not listed according to the ib of nivolumab, in this context the event is considered expected since the verbatim characterizes diarrhoea and refers to the immune-mediating effect of nivolumab, which is well-known.The causality assessment remains unchanged as possibly related to nivolumab and not related for sir-spheres microspheres, mapping and implant procedures.With follow-up information received on 13-jul-2018 information on hospitalization dates, medical history, concomitant medication, and treatment of the diarrhea was provided, and the outcome was reported as resolved.Histopathological results revealed lymphocytic colitis.The date of the last administration of nivolumab prior to the event was reported.Even though nivolumab was lastly administered 4 weeks prior to the event, the temporal relationship remains plausible in view of the long elimination half-life of nivolumab and the assumed immune-mediated etiology of the event.The causality for the immunorelated diarrhea was assessed by the investigator as not related to sir-spheres microspheres, mapping and implant procedures, and unlikely related to nivolumab.The sponsor's causality assessment remains unchanged as possibly related to nivolumab and not related to sir-spheres microspheres, mapping and implant procedures.

• Brand Name: SIR-SPHERES® Y-90 RESIN MICROSPHERES
• Type of Device: MICROSPHERES
• Manufacturer (Section D): SIRTEX TECHNOLOGY PTY LTD / SIRTEX MEDICAL LIMITED; level 33; 101 miller street; north sydney, 2060 ; AS 2060
• MDR Report Key: 7497586
• MDR Text Key: 107693126
• Report Number: 3005579300-2018-00005
• Device Sequence Number: 1
• Product Code: NAW
• Combination Product (y/n): N
• Number of Events Reported: 1
• Summary Report (Y/N): N
• Report Source: Manufacturer
• Source Type: foreign,health professional,s
• Type of Report: Initial,Followup,Followup
• Report Date: 07/25/2018

1 Device was Involved in the Event

1 Patient was Involved in the Event

• Is this an Adverse Event Report?: Yes
• Is this a Product Problem Report?: No
• Device Operator: Health Professional
• Device Lot Number: MA410V02
• Was the Report Sent to FDA?: No
• Initial Date Manufacturer Received: 04/17/2018
• Initial Date FDA Received: 05/09/2018
• Supplement Dates Manufacturer Received: 06/18/2018; 07/13/2018
• Supplement Dates FDA Received: 07/06/2018; 08/01/2018
• Is This a Reprocessed and Reused Single-Use Device?: No
• Patient Sequence Number: 1
• Treatment: CAPTOPRIL; ENALAPRIL/HYDROCHLOROTHIAZIDE; NIVOLUMAB; NIVOLUMAB; NIVOLUMAB; NIVOLUMAB
• Patient Outcome(s): Hospitalization
• Patient Age: 75 YR