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

Model Number UNKNOWN

Device Problems Adverse Event Without Identified Device or Use Problem (2993); Insufficient Information (3190)

Patient Problems Biliary Cirrhosis (1736); Death (1802); Edema (1820); Hepatitis (1897); Liver Damage/Dysfunction (1954); Peritonitis (2252); Therapeutic Response, Decreased (2271); Toxicity (2333); Ascites (2596)

Event Type  Death  

Event Description

Reild (radiation-induced liver disease) [radiation hepatitis].Decompensated cirrhosis [hepatic cirrhosis].Spontaneous bacterial peritonitis [peritonitis bacterial].Partial response of all four lesions [therapeutic response decreased].Case description: information received on 29-mar-2017: this spontaneous medical device report was received from a literature article by braat et al.Entitled "hepatobiliary scintigraphy may improve radioembolization treatment planning in hcc patients" published in the ejnmmi research journal regarding a homeless (b)(6) male patient.The patient was initially included in a multicenter randomised controlled trial in 2012 comparing tace and transarterial radioembolization (re) in patients with unresectable hepatocellular carcinoma (hcc) (the trace study; nct01381211).The patient's medical history included liver cirrhosis due to alcohol abuse, screening with dynamic contrast-enhanced magnetic resonance imaging (mri), bone scintigraphy and angiography and a 99mtc-mebrofenin hepatobiliary scintigraphy that showed a visually fairly homogenous 99mtcmebrofenin uptake with a defect in segment 8, corresponding to the hcc.On an unspecified date, liver mri revealed four hypervascular lesions in segments 1 (1.0 cm), 5 (4.4 cm) and 8 (3.2 and 0.8 cm), consistent with multifocal hcc (tumour involvement 1%).Coexisting portal hypertension and a moderate amount of ascites were also present, but no portal vein thrombus.At diagnosis, he had decompensated cirrhosis.The patient had a child-pugh grade b8 at treatment (albi grade 3).The patient's concomitant medications included tc-99m macroaggregated albumin intra-arterially injected for planar scintigraphy and single-photon emission computed tomography (spect)/ ct used to calculate the lung shunt fraction (lsf) and to detect other extrahepatic deposition.The patient also received tc-99 mebrofenin for the hepatobiliary scintigraphies performed at the baseline and during the 3-month follow-up evaluation.The lung shunt fraction (lsf) was calculated at 4% using spect/ ct.On an unspecified date, 5 months after hcc diagnosis, decompensated cirrhosis was recompensated and the patient was treated with therasphere (yttrium-90 glass microspheres), 2.5 gbq, target dose 100 gy, in the right liver lobe for hcc (lot numbers and expiration dates were not reported).The endhole catheter tip was positioned at the bifurcation of the anterior and posterior right hepatic artery.The overdosage of the posterior sector was therefore most likely due to preferential flow.On an unspecified date, the posttreatment 90y-pet/ct showed reasonable targeting, but also a relatively large amount of activity in the tumour-free segments 6 and 7 with an average absorbed dose of 91 gy.The absorbed dose for the tumours in segments 1, 5 and 8 was 226, 63 and 227 gy, respectively.The absorbed dose of the smallest tumour (0.8 cm) could not reliably be measured.On an unspecified date, fourteen days after treatment, he was readmitted with increasing ascites and peripheral oedema, consistent with decompensated cirrhosis.The outcome was unknown.On an unspecified date, two days later, he developed a spontaneous bacterial peritonitis, successfully managed with albumin suppletion and antibiotics.At 3-month follow-up, his liver function had further declined to child pugh grade c11, with a grade 3 bilirubin toxicity.Follow-up mri at that time showed a partial response of all four lesions, consistent with the decrease in afp levels.However, also massive ascites and shrinkage of the liver with increased arterial enhancement of the treated lobe and decreased 99mtc-mebrofenin uptake were noted.At 3-month follow-up, his liver function had declined to 0.6%/min/m2 (1.8%/min/m2 at baseline).The pre-re liver function was mainly located in the right hemiliver (1.6%/min/m2).After re, this declined to 0.4%/min/m2, without compensatory function increase of the left hemiliver (stable at 0.2%/min/m2).On an unspecified date, the patient died 4 months after re treatment due to definite radioembolization-induced liver disease (reild).The authors did not assess the seriousness of the events however considered that the rapid clinical deterioration was due to reild.Additionally, the authors considered that the pre-treatment clinical, laboratory and imagining parameters were within acceptable limits for treatment, but did not predict the severe toxicity encountered, although the cases involved lobar treatments only.The company considered the event radioembolization-induced liver disease to be serious (fatal), the event decompensated cirrhosis as serious (hospitalization), the event spontaneous bacterial peritonitis as medically significant and partial response as non-serious.This case is linked to cases btg01211 and btg01213 from the same literature article.Follow-up will be requested.Case comment: radiation hepatitis, hepatic cirrhosis and peritonitis bacterial are considered anticipated according to therasphere current reference safety information whereas therapeutic response decreased is unanticipated.In line with the assessment made by the author, the company considered that radiation hepatitis and hepatic cirrhosis are related to the use of therasphere based upon temporal relationship and knowledge of the product.However, the patient's medical history of liver cirrhosis due to alcohol abuse might have contributed to the events.In the absence of assessment made by the reporter, the company considered that peritonitis bacterial was related to the use of therasphere as it cannot be ruled out.In line with the assessment made by the author, the company considered that therapeutic response decreased is not related to the use of therasphere and rather related to underlying disease.There was no report of device deficiency or malfunction.This single case report does not modify the risk benefit balance of therasphere.The company is continuously monitoring all respective reports received and, based on cumulative experience, will reevaluate the available evidence on an ongoing basis.

Event Description

Reild (radiation-induced liver disease) [radiation hepatitis], decompensated cirrhosis [hepatic cirrhosis], spontaneous bacterial peritonitis [peritonitis bacterial], partial response of all four lesions [therapeutic response decreased].Case description: information received on 29-mar-2017: this spontaneous medical device report was received from a literature article by braat et al.Entitled "hepatobiliary scintigraphy may improve radioembolization treatment planning in hcc patients" published in the ejnmmi research journal regarding a homeless (b)(6) male patient.The patient was initially included in a multicenter randomised controlled trial in 2012 comparing tace and transarterial radioembolization (re) in patients with unresectable hepatocellular carcinoma (hcc) (the trace study; (b)(4)).The patient's medical history included liver cirrhosis due to alcohol abuse, screening with dynamic contrast-enhanced magnetic resonance imaging (mri), bone scintigraphy and angiography and a 99mtc-mebrofenin hepatobiliary scintigraphy that showed a visually fairly homogenous 99mtcmebrofenin uptake with a defect in segment 8, corresponding to the hcc.On an unspecified date, liver mri revealed four hypervascular lesions in segments 1 (1.0 cm), 5 (4.4 cm) and 8 (3.2 and 0.8 cm), consistent with multifocal hcc (tumour involvement 1%).Coexisting portal hypertension and a moderate amount of ascites were also present, but no portal vein thrombus.At diagnosis, he had decompensated cirrhosis.The patient had a child-pugh grade b8 at treatment (albi grade 3).The patient's concomitant medications included tc-99m macroaggregated albumin intra-arterially injected for planar scintigraphy and single-photon emission computed tomography (spect)/ ct used to calculate the lung shunt fraction (lsf) and to detect other extrahepatic deposition.The patient also received tc-99 mebrofenin for the hepatobiliary scintigraphies performed at the baseline and during the 3-month follow-up evaluation.The lung shunt fraction (lsf) was calculated at 4% using spect/ ct.On an unspecified date, 5 months after hcc diagnosis, decompensated cirrhosis was recompensated and the patient was treated with therasphere (yttrium-90 glass microspheres), 2.5 gbq, target dose 100 gy, in the right liver lobe for hcc (lot numbers and expiration dates were not reported).The endhole catheter tip was positioned at the bifurcation of the anterior and posterior right hepatic artery.The overdosage of the posterior sector was therefore most likely due to preferential flow.On an unspecified date, the posttreatment 90y-pet/ct showed reasonable targeting, but also a relatively large amount of activity in the tumour-free segments 6 and 7 with an average absorbed dose of 91 gy.The absorbed dose for the tumours in segments 1, 5 and 8 was 226, 63 and 227 gy, respectively.The absorbed dose of the smallest tumour (0.8 cm) could not reliably be measured.On an unspecified date, fourteen days after treatment, he was readmitted with increasing ascites and peripheral oedema, consistent with decompensated cirrhosis.The outcome was unknown.On an unspecified date, two days later, he developed a spontaneous bacterial peritonitis, successfully managed with albumin suppletion and antibiotics.At 3-month follow-up, his liver function had further declined to child pugh grade c11, with a grade 3 bilirubin toxicity.Follow-up mri at that time showed a partial response of all four lesions, consistent with the decrease in afp levels.However, also massive ascites and shrinkage of the liver with increased arterial enhancement of the treated lobe and decreased 99mtc-mebrofenin uptake were noted.At 3-month follow-up, his liver function had declined to 0.6%/min/m2 (1.8%/min/m2 at baseline).The pre-re liver function was mainly located in the right hemiliver (1.6%/min/m2).After re, this declined to 0.4%/min/m2, without compensatory function increase of the left hemiliver (stable at 0.2%/min/m2).On an unspecified date, the patient died 4 months after re treatment due to definite radioembolization-induced liver disease (reild).The authors did not assess the seriousness of the events however considered that the rapid clinical deterioration was due to reild.Additionally, the authors considered that the pre-treatment clinical, laboratory and imagining parameters were within acceptable limits for treatment, but did not predict the severe toxicity encountered, although the cases involved lobar treatments only.The company considered the event radioembolization-induced liver disease to be serious (fatal), the event decompensated cirrhosis as serious (hospitalization), the event spontaneous bacterial peritonitis as medically significant and partial response as non-serious.This case is linked to cases (b)(4) from the same literature article.Follow-up will be requested.Additional information on 02-may-2017: follow up information has been sought to further investigate the events.As of 02-may-2017, no additional information has been received.The case is considered lost to follow up.No device failure has been identified as a result of this adverse events.It has been assessed that no corrective action is necessary at this time and the report is considered final.Case comment: radiation hepatitis, hepatic cirrhosis and peritonitis bacterial are considered anticipated according to therasphere current reference safety information whereas therapeutic response decreased is unanticipated.In line with the assessment made by the author, the company considered that radiation hepatitis and hepatic cirrhosis are related to the use of therasphere based upon temporal relationship and knowledge of the product.However, the patient's medical history of liver cirrhosis due to alcohol abuse might have contributed to the events.In the absence of assessment made by the reporter, the company considered that peritonitis bacterial was related to the use of therasphere as it cannot be ruled out.In line with the assessment made by the author, the company considered that therapeutic response decreased is not related to the use of therasphere and rather related to underlying disease.There was no report of device deficiency or malfunction.This single case report does not modify the risk benefit balance of therasphere.The company is continuously monitoring all respective reports received and, based on cumulative experience, will reevaluate the available evidence on an ongoing basis.

Manufacturer Narrative

The case comment reported in the initial and follow up 1 report remains unchanged.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 04 may 2018.Refer to initial report and follow up #1 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 19 mar 2018.Limited information was reported in response to the request.Additional information reported: - hepatic tumor identification, including the kind of tumor, tumor burden in the liver, date and method of identification: hcc, multifocal right lobe, largest tumor 4.4 cm, cirrhosis, child-pugh b8 - calculation formula for required dose assessment: mird; 100 gy, 2.5 gbq - pre-procedural hepatic angiogram finding, and follow up procedure: uncomplicated, maa rha.- lung shunt: 4% lung shunt fraction.- follow up data, at the day of administration, in 1, 4, 8, 12 weeks and the significant findings in the follow up: at 3 months bilirubin grade 3 tox, ascites, child-pugh c11.On mri progression of tumors.Death 4 months after treatment.- description of sae events, significant finding, lab data, mitigation process, and the patient outcome: reild (radioembolixation induced liver disease).- assessment of the relationship to the device: most likely related to therasphere.

• 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: 6525687
• MDR Text Key: 73823587
• Report Number: 3002124543-2017-00015
• Device Sequence Number: 1
• Product Code: NAW
• Combination Product (y/n): N
• Reporter Country Code: NL
• PMA/PMN Number: H980006
• Number of Events Reported: 1
• Summary Report (Y/N): N
• Report Source: Manufacturer
• Source Type: foreign,health professional,l
• Reporter Occupation: Physician
• Type of Report: Initial,Followup,Followup
• Report Date: 05/04/2018

1 Device was Involved in the Event

1 Patient was Involved in the Event

• Date FDA Received: 04/27/2017
• Is this an Adverse Event Report?: Yes
• Is this a Product Problem Report?: No
• Device Operator: Physician
• Device Model Number: UNKNOWN
• Device Lot Number: UNKNOWN
• Was Device Available for Evaluation?: No
• Is the Reporter a Health Professional?: Yes
• Was the Report Sent to FDA?: No
• Date Manufacturer Received: 05/04/2018
• 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
• Treatment: TECHNETIUM (99M TC) DMSA (TECHNETIUM (99M TC) DMSA
• Patient Outcome(s): Death; Hospitalization; Other
• Patient Age: 57 YR