MAUDE Adverse Event Report: BIOCOMPATIBLES UK LTD THERASPHERE; YTTRIUM-90 GLASS MICROSPHERES

Model Number N/A

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

Patient Problems Abdominal Pain (1685); Death (1802); Diarrhea (1811); Encephalopathy (1833); Liver Damage/Dysfunction (1954); Thrombosis (2100); Pseudoaneurysm (2605); Vascular Dissection (3160); Multiple Organ Failure (3261)

Event Date 02/02/2017

Event Type  Death  

Event Description

Worsening liver function/progressive hepatic failure [disease progression]; right hepatic artery pseudoaneurysm [vascular pseudoaneurysm]; portal vein thrombosis [portal vein thrombosis]; right hepatic artery dissected [artery dissection]; encephalopathy [encephalopathy]; right upper quadrant pain [abdominal pain upper].Case description: initial information received on 20-mar-2017 and additional information received on 21-mar-2017, 23-mar-2017 and on 11-apr-2017: this spontaneous medical device report was received from a physician via a company representative concerning a (b)(6) female patient.The patient's medical history included bilobar carcinoid tumour diagnosed in 2007, selective left segment 2/3 and segment 4 bland embolization, using 7/10 vial 45-150 micron pva in 2008, neuropathy caused by chemotherapy and a primary tumour in small bowel with initial surgery on (b)(6) 2010.On an unknown date, the patient underwent an exploratory laparotomy at distal ileum, right hemicolectomy with mesenteric mass reception and cholecystectomy.The patient was subsequently treated with chemoembolization three times to treat disease in liver on (b)(6) 2010, in (b)(6), followed by sandostatin injections.Carcinoid syndrome was well controlled until her diarrhoea returned on (b)(6) 2016.Dota-noc pet scan was performed on (b)(6) 2016 and showed evidence of disease progression, primarily in the liver.The patient's concomitant medications were not reported.On (b)(6) 2016, an unspecified procedure was performed without complications.On (b)(6) 2016, the patient received therasphere (lot number was unknown and expiration date was not reported) in right hepatic artery "apparently" without complication to treat right lobe liver metastases.The activity planned was 57 mci and the delivered dose was 56.7 mci.The total dose delivered to right lobe of the liver was 109.4 gy.The lung shunt fraction (lsf) was calculated at 8.9%.On (b)(6) 2016, the patient was doing well in clinic.As such, treatment of the patient's left lobe metastases was planned and scheduled.On (b)(6) 2016, the patient received therasphere (lot number 1699321-vial 68, calibration date 30-oct-2016 and expiration date 11-nov-2016) in the left hepatic artery for left lobe liver metastases.The activity planned was 95 mci and the delivered dose was 93.7 mci.The total dose delivered to the left lobe of the liver was 107.5 gy, using same calculated lsf of 8.9%.On (b)(6) 2016, an arteriogram was performed and showed only slight narrowing of the artery at the site of right hepatic artery therasphere administration.On (b)(6) 2017, the patient was admitted to the emergency room (er) with right upper quadrant (ruq) pain but she reported that her pain was decreasing when she was seen in clinic on (b)(6) 2017.At that time, her total bilirubin (tb) was at 1.8, slightly higher than at the pre-treatment time.At the same time, mri demonstrated response to treatment: multiple metastatic lesions were seen in the liver and a large metastatic lesion in the segment 4 demonstrating significant necrotic changes likely related to recent treatment.There was mass effect of the biliary ductal system and portal vein at the porta-hepatis.On an unspecified date, the patient went home and was reportedly doing well.In early (b)(6) 2017, she developed symptoms of encephalopathy while vacationing and was hospitalized.Ct scan was performed on (b)(6) 2017 and demonstrated portal vein thrombosis and a right hepatic artery pseudoaneurysm.She was evaluated for multivisceral transplant, but was found not to be a candidate due to the presence of extra-abdominal disease.She was treated symptomatically and her encephalopathy improved, so she was discharged on (b)(6) 2017.However, she was readmitted a few days later with worsening liver function.On (b)(6) 2017, total bilirubin was at 16.3.On the same date, given her progressive hepatic failure, it was attempted to place a stent graft in her right hepatic artery to treat the pseudoaneurysm and thus to allow administration of anticoagulation therapy to treat her thrombosed portal vein.However, it was not possible to place that stent graft, and during the procedure, the right hepatic artery was dissected, and the dissection progressed retrograde to involve her left hepatic artery.It was not possible to reestablish flow to the liver.On (b)(6) 2017, the patient died due to liver failure.The reporter stated that the pseudoaneurysm was "at or near" the site of therasphere administration, therefore was potentially related to the device.The reporter also acknowledged the multiple previous embolic procedures and a carcinoid diagnosis increased the risk of vascular injury.A quality investigation was performed of lot number 1699321: the lot met all of its release criteria.There were no deviations associated with this lot that would impact final product quality or risk to patient or end user safety.The radionuclidic impurities passed all requirements.The lot met all qc release requirements.No follow-up information is expected.The case is final.Case comment: the company considered that encephalopathy, abdominal pain upper and portal vein thrombosis are not related to the use of therasphere and rather associated with disease progression.Additionally, disease progression occured in liver carcinoma in patient with incurable liver cancer who developed portal vein thrombosis, liver failure, encephalopathy (and the symptoms of them) suggesting end stage disease which led to the patient's death.Thus the company considered disease progression not related to therasphere.In agreement with the assessment made by the reporter, the company considered that vascular pseudoaneurysm was related to the use of therasphere due to location "at or near" to the site of therasphere administration.Artery dissection occurred as a complication of pseudoaneurysm treatment with stent graft and therefore was considered as not related to the use of therasphere.Carcinoid tumor, multiple previous embolization and chemoembolization procedures might have predisposed the patient to vascular injury (vascular pseudoaneurysm) which could have contributed to the complication of the procedure/device.There was no report of device deficiency or malfunction.

Event Description

Event verbatim [preferred term] (related symptoms if any separated by commas).Worsening liver function/progressive hepatic failure [disease progression].Right hepatic artery pseudoaneurysm [vascular pseudoaneurysm].Portal vein thrombosis [portal vein thrombosis].Right hepatic artery dissected [artery dissection].Encephalopathy [encephalopathy].Right upper quadrant pain [abdominal pain upper].Case description: initial information received on (b)(4) 2017 and additional information received on (b)(4) 2017: this spontaneous medical device report was received from a physician via a company representative concerning a (b)(6)-year-old female patient.The patient's medical history included bilobar carcinoid tumour diagnosed in 2007, selective left segment 2/3 and segment 4 bland embolization, using 7/10 vial 45-150 micron pva in 2008, neuropathy caused by chemotherapy and a primary tumour in small bowel with initial surgery on (b)(6) 2010.On an unknown date, the patient underwent an exploratory laparotomy at distal ileum, right hemicolectomy with mesenteric mass reception and cholecystectomy.The patient was subsequently treated with chemoembolization three times to treat disease in liver on (b)(6) 2010, in (b)(6), followed by sandostatin injections.Carcinoid syndrome was well controlled until her diarrhoea returned on (b)(6) 2016.Dota-noc pet scan was performed on (b)(6) 2016 and showed evidence of disease progression, primarily in the liver.The patient's concomitant medications were not reported.On (b)(6) 2016, an unspecified procedure was performed without complications.On (b)(6) 2016, the patient received therasphere (lot number was unknown and expiration date was not reported) in right hepatic artery "apparently" without complication to treat right lobe liver metastases.The activity planned was 57 mci and the delivered dose was 56.7 mci.The total dose delivered to right lobe of the liver was 109.4 gy.The lung shunt fraction (lsf) was calculated at 8.9%.On (b)(6) 2016, the patient was doing well in clinic.As such, treatment of the patient's left lobe metastases was planned and scheduled.On (b)(6) 2016, the patient received therasphere (lot number 1699321-vial 68, calibration date 30-oct- 2016 and expiration date 11-nov-2016) in the left hepatic artery for left lobe liver metastases.The activity planned was 95 mci and the delivered dose was 93.7 mci.The total dose delivered to the left lobe of the liver was 107.5 gy, using same calculated lsf of 8.9%.On (b)(6) 2016, an arteriogram was performed and showed only slight narrowing of the artery at the site of right hepatic artery therasphere administration.On (b)(6) 2017, the patient was admitted to the emergency room (er) with right upper quadrant (ruq) pain but she reported that her pain was decreasing when she was seen in clinic on (b)(6) 2017.At that time, her total bilirubin (tb) was at 1.8, slightly higher than at the pre-treatment time.At the same time, mri demonstrated response to treatment: multiple metastatic lesions were seen in the liver and a large metastatic lesion in the segment 4 demonstrating significant necrotic changes likely related to recent treatment.There was mass effect of the biliary ductal system and portal vein at the porta-hepatis.On an unspecified date, the patient went home and was reportedly doing well.In early (b)(6) 2017, she developed symptoms of encephalopathy while vacationing and was hospitalized.Ct scan was performed on (b)(6) 2017 and demonstrated portal vein thrombosis and a right hepatic artery pseudoaneurysm.She was evaluated for multivisceral transplant, but was found not to be a candidate due to the presence of extra-abdominal disease.She was treated symptomatically and her encephalopathy improved, so she was discharged on (b)(6) 2017.However, she was readmitted a few days later with worsening liver function.On (b)(6) 2017, total bilirubin was at 16.3.On the same date, given her progressive hepatic failure, it was attempted to place a stent graft in her right hepatic artery to treat the pseudoaneurysm and thus to allow administration of anticoagulation therapy to treat her thrombosed portal vein.However, it was not possible to place that stent graft, and during the procedure, the right hepatic artery was dissected, and the dissection progressed retrograde to involve her left hepatic artery.It was not possible to reestablish flow to the liver.On (b)(6) 2017, the patient died due to liver failure.The reporter stated that the pseudoaneurysm was "at or near" the site of therasphere administration, therefore was potentially related to the device.The reporter also acknowledged the multiple previous embolic procedures and a carcinoid diagnosis increased the risk of vascular injury.A quality investigation was performed of lot number 1699321: the lot met all of its release criteria.There were no deviations associated with this lot that would impact final product quality or risk to patient or end user safety.The radionuclidic impurities passed all requirements.The lot met all qc release requirements.No follow-up information is expected.The case is final.Follow-up information received on 09-aug-2017: the complaint-related lot number was inadvertently reported to be administered on the (b)(6) 2016 instead of (b)(6) 2016.On (b)(6)2016, the patient received therasphere (lot number 1699321-vial 68, calibration date 30-oct-2016 and expiration date 11-nov-2016).On (b)(6) 2016, the patient received therasphere (lot number 1699385, vial unknown, not complaint related).At the time of this final report, no further information was outstanding or expected.Case comment: the company considered that encephalopathy, abdominal pain upper and portal vein thrombosis are not related to the use of therasphere and rather associated with disease progression.Additionally, disease progression occured in liver carcinoma in patient with incurable liver cancer who developed portal vein thrombosis, liver failure, encephalopathy (and the symptoms of them) suggesting end stage disease which led to the patient's death.Thus the company considered disease progression not related to therasphere.In agreement with the assessment made by the reporter, the company considered that vascular pseudoaneurysm was related to the use of therasphere due to location "at or near" to the site of therasphere administration.Artery dissection occurred as a complication of pseudoaneurysm treatment with stent graft and therefore was considered as not related to the use of therasphere.Carcinoid tumor, multiple previous embolization and chemoembolization procedures might have predisposed the patient to vascular injury (vascular pseudoaneurysm) which could have contributed to the complication of the procedure/device.There was no report of device deficiency or malfunction.

Manufacturer Narrative

The case comment reported in the initial and follow up 1 report remains unchanged.Although the assessment of relationship was previously reported, the physician reiterated that the right hepatic artery pseudoaneurysm was most likely related to the device, as the pseudoaneurysm occurred at the site of right hepatic artery administration.While that pseudoaneurysm could've occurred spontaneously in that area, the physician could not attribute the co-location as coincidence.There was no device malfunction reported.No additional information will be reported in association with this case.

Event Description

This is a follow up #2 submitted to report additional information received from the physician on 26 mar 2018.Refer to initial report for event description.Following the submission of an annual report to the fda on 23 feb 2018, the fda requested additional detailed patient and procedure information to aid in reviewing the saes reported in the annual update.The request for additional information was sent to the physician via email on 20 mar 2018.Limited information was reported in response to the request.Additional information reported: - additional medical history: the patient did not have (b)(6); she admitted to social drinking, was not an alcoholic; while she was not diagnosed with cirrhosis, given her long history of disease and multiple previous embolic procedures, it cannot be excluded.- hepatic tumor identification, including the kind of tumor, tumor burden in the liver, date and method of identification: metastatic disease.The liver was full of tumor in both lobes.Method of identification: dotanoc pet/ct on (b)(6) 2016.- calculation formula for required dose assessment: right lobe calculation: target volume 830.0 cc, total liver mass 0.855 kg, desired dose 110 gy, lung shunt fraction 8.9%, anticipated resudual waste 2.00%, previous dose to the lungs 0 gy, required activity of administration 2.11 gbq, calculated dose to the lungs 9.19 gy, dose limit to the lungs per treatment 30 gy, cumulative dose to lungs 9.19 gy, cumulative dose limit to lungs 50 gy, dose size selected 7.5 gbq, date and time for administration friday, (b)(6) at 0900.Left lobe calculation: target volume 1400.0 cc, total liver mass 1.442 kg, desired dose 109 gy, lung shunt fraction 8.9%, anticipated resudual waste 2.00%, previous dose to the lungs 0 gy, required activity of administration 3.52 gbq, calculated dose to the lungs 15.36 gy, dose limit to the lungs per treatment 30 gy, cumulative dose to lungs 15.36 gy, cumulative dose limit to lungs 50 gy, dose size selected 9.5 gbq, date and time for administration thursday (b)(6) at 8 - assessment of the relationship to the device: assessment reported in the initial and follow up report.Confirmation received that the right hepatic artery pseudoaneurysm is most likely related to the device, as the pseudoaneurysm occurred at the site of right hepatic artery administration.While that pseudoaneurysm could've occurred spontaneously in that area, the physician could not attribute the co-location as coincidence.

• Brand Name: THERASPHERE
• Type of Device: YTTRIUM-90 GLASS MICROSPHERES
• Manufacturer (Section D): BIOCOMPATIBLES UK LTD; farnham business park; weydon lane; farnham, surrey GU9 8 QL; UK GU9 8QL
• Manufacturer (Section G): BIOCOMPATIBLES UK LTD; farnham business park; weydon lane; farnham, surrey GU9 8 QL; UK GU9 8QL
• Manufacturer Contact: sandra bausback ; 300 four falls corp cntr - 380; 300 conshohocken st. rd.; west conshohocken, PA 19428-2998 ; 6103311537
• MDR Report Key: 6502906
• MDR Text Key: 73102193
• Report Number: 3002124543-2017-00013
• Device Sequence Number: 1
• Product Code: NAW
• Combination Product (y/n): N
• Reporter Country Code: US
• PMA/PMN Number: H980006
• Number of Events Reported: 1
• Summary Report (Y/N): N
• Report Source: Manufacturer
• Source Type: company representative,health
• Reporter Occupation: Physician
• Type of Report: Initial,Followup,Followup
• Report Date: 03/26/2018

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: Physician
• Device Expiration Date: 11/11/2016
• Device Model Number: N/A
• Device Lot Number: 1699321
• Was Device Available for Evaluation?: No
• Is the Reporter a Health Professional?: Yes
• Was the Report Sent to FDA?: No
• Initial Date Manufacturer Received: 03/20/2017
• Initial Date FDA Received: 04/19/2017
• Supplement Dates Manufacturer Received: 08/09/2017; 03/26/2018
• Supplement Dates FDA Received: 09/04/2017; 04/23/2018
• Was Device Evaluated by Manufacturer?: Device Not Returned to Manufacturer
• Is the Device Single Use?: Yes
• Is This a Reprocessed and Reused Single-Use Device?: No
• Type of Device Usage: Initial
• Patient Sequence Number: 1
• Patient Outcome(s): Death; Hospitalization; Other; Required Intervention
• Patient Age: 68 YR