| Lot Number 1899048 |
| Device Problem
Adverse Event Without Identified Device or Use Problem (2993)
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| Patient Problem
No Code Available (3191)
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| Event Date 10/04/2018 |
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Event Type
Injury
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Event Description
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This case has been also reported as a usade associated with the ide.3 therasphere® vials were used to treat this patient, it cannot be determined which device contributed to this clinically significant event.Refer to mdr 3002124543-2018-00046 and 3002124543-2018-00048 for the other device associated with this event.Mfr report number: 3002124543-2018-00047.(b)(4).Last sae report: 19 oct 2018.Sae: symptomatic non-cirrhotic portal hypertension definitely related to sirt (therasphere) (non-cirrhotic portal hypertension).This report concerns subject (b)(6), a male subject born in (b)(6), who was enrolled in study(b)(6) in subjects with metastatic colorectal carcinoma of the liver who have failed first line chemotherapy".On (b)(6) 2018, the subject was randomized to receive treatment with therasphere® for metastatic colorectal carcinoma and second-line chemotherapy.On (b)(6) 2018, the subject received first cycle of second-line chemotherapy, folfiri regimen (irinotecan 337 mg, folinic acid 749 mg and fluorouracil 749 mg and 4495 mg intravenous (iv) which completed on (b)(6) 2018).On (b)(6) 2018, the subject received treatment with total 3 vials of therasphere®.The right hepatic lobe was treated with two vials (activity of 5 and 3.5 gbq/lot no 1899055, expiry date: 23 feb 2018 and 1899048, expiry date: 16 feb 2018) at a dose of 119.89 gy and 110.91 gy (segment 8 only).One vial was administered in the left hepatic lobe (vial activity of 6 gbq/lot no 1899048, expiry date: 16 feb 2018) at a dose 115.34 gy.On (b)(6) 2018, the subject received most recent cycle (fourteenth) of second-line chemotherapy, folfiri regimen (irinotecan 236 mg iv, folinic acid 524 mg iv and fluorouracil 524 mg iv and 3147 mg iv which completed on (b)(6) 2018, prior to the event.The subject was non-alcoholic and had no other relevant medical history except previous exposure to oxaliplatin.On (b)(6) 2018, the subject had albumin of 3.4 mg/dl (normal range: 3.5 to 5.0).On (b)(6) 2018, the subject had albumin of 3.3 mg/dl (normal range: 3.5 to 5.0) which was considered as possibly related to the experimental treatment.The subject's albumin level kept on worsening, had no proteinuria and no disease progression.Hypoalbuminemia had not improved despite withdrawing of aflibercept.On (b)(6) 2018, the subject experienced symptoms related to hypoalbuminemia/ hepatic failure (which was the first event to be noticed with good clinical condition with no signs of encephalopathy) and hence a gastroscopy was scheduled to evaluate presence of esophageal varices which would also reveal portal hypertension.Gastroscopy revealed varices.The subject also had clinical ascites which prompted to withdraw second line chemotherapy and required diuretics.A computerized tomogram (ct scan) was performed on an unspecified date for which the subject was considered for best examination to be performed including biopsy.Laboratory test showed glucose 145 mg/dl (normal range: 60 to 100), creatinine 0.55 mg/dl (normal range: 0.60 to 1.20), calcium 8.4 mg/dl (normal range: 8.7 to 10.3), bilirubin total 1.4 mg/dl (normal range: 0.3 to 1.1) and aspartate transaminase (ast) 84 u/l (normal range: 6 to 40).Repeat laboratory test on the same day ((b)(6) 2018) showed glucose 146 mg/dl (normal range: 60 to 100), estimated glomerular filtration rate > 90 ml.Min/1.73m2, protein total 5.2 g/dl (normal range: 6 to 8), albumin 2.7 g/dl (normal range: 3.5 to 5), calcium 8.1 mg/dl (normal range: 8.7 to 10.3), bilirubin total 1.6 mg/dl (normal range: 0.3 to 1.1), lactate dehydrogenase (ldh) 710 u/l (normal range: 230 to 460), alanine aminotransferase (alt) 56 u/l (normal range: 6 to 40), aspartate transaminase (ast) 80 u/l (normal range: 6 to 40), alkaline phosphatase 220 u/l (normal range: 40 to 128), gamma glutamyltransferase 317 u/l (normal range: 8 to 61), leukocytes 2.84 x 10^3/microl (normal range: 4 to 11.5), lymphocytes 0.7 10^3/microl (normal range: 1.2 to 4), neutrophils 53.4 %, lymphocytes 24.3 %, monocytes 17.3 %, eosinophils 3.5 %, basophils 1.1 %, mean corpuscular hemoglobin concentration (mchc) 30.7 g/dl (normal range: 32 to 36), red cell distribution width (rdw) 20.20 % (normal range: 8 to 14.8), platelets 78 10^3/microl (normal range: 150 to 400) and platelets distribution width (pdw) 11 %.On (b)(6) 2018, the subject was diagnosed with symptomatic non-cirrhotic portal hypertension definitely related to sirt (selective internal radiation therapy) (plus chemotherapy), esophageal varices, ascites and hypoalbuminemia.The investigator drew the diagnosis of non-cirrhotic portal hypertension based on previous experience with determination of portal pressure (in two cases) and a liver biopsy demonstrating nodular regenerative hyperplasia (similar to sos) and after reviewing the scientific literature.Due to this gastroscopy was performed suspecting portal hypertension which was confirmed.Opportunity of a liver biopsy will be assessed in the subject.At the time of this report, the event of symptomatic non-cirrhotic portal hypertension definitely related to sirt (therasphere) was not resolved.The subject continued participation in the study.Treatment with second line chemotherapy was stopped temporarily due to this event.The investigator assessed the event of symptomatic non-cirrhotic portal hypertension definitely related to sirt (therasphere) as grade-3 (severe) in intensity and serious due other: clinically significant and definitely related to study device, unrelated to study procedure, probably related second line chemotherapy and other: first line chemotherapy.To the investigator, hypoalbuminemia was related to non-cirrhotic portal hypertension which in turn was related to previous first line chemotherapy treatment (oxaliplatin) and sirt as these therapies have been related to portal hypertension.The role of irinotecan was not known but was still considered as related.The event was considered as definitely related to study device due to the rarity of the event in absence of sirt and progression in patients with second line treatment, however, not so rare when sirt was administered to patient in the first line treatment.The company assessed the event as possibly related to study device, second line chemotherapy (folfiri) and possibly related to first line chemotherapy (folfox regimen).The event was considered as not related to study procedure.A supplemental report will be submitted if additional relevant information is received.
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Event Description
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3 therasphere® vials were used to treat this patient, it cannot be determined which device contributed to this clinically significant event.Refer to mdr 3002124543-2018-00046 and 3002124543-2018-00048 for the other device associated with this event.This case has been also reported as a usade associated with the ide.This is a follow-up report to update repeat biopsy results done on (b)(6) 2019.Internal mcn: (b)(4), ide: (b)(4), subject: (b)(6), last sae report: (b)(6) 2019.Sae: symptomatic non-cirrhotic portal hypertension definitely related to sirt (therasphere) (non-cirrhotic portal hypertension).On (b)(6) 2019, new liver biopsy was performed, which revealed liver cylinders with extensive hepatocellular necrosis and septal fibrosis.No additional information is expected at this time.
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Event Description
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This is a follow-up report to update aflibercept therapy details, clinical course of the event including laboratory details, symptoms and outcome from (b)(6) 2018 to (b)(6) 2018 and company causality assessment description.Internal mcn: (b)(4), ide: (b)(4), subject: (b)(6), last sae report: 03 dec 2018.Sae: symptomatic non-cirrhotic portal hypertension definitely related to sirt (therasphere) (non-cirrhotic portal hypertension).On (b)(6) 2018, a biological (aflibercept) was added to the second-line chemotherapy, folfiri regimen at a dose of 313 mg iv.From (b)(6) 2018 to (b)(6) 2018, the subject received cycles of second-line chemotherapy, folfiri regimen and aflibercept was added at chemotherapy cycle number 3-5-6-7-9-10-12-13.Aflibercept was not added to cycle 8 on (b)(6) 2018, at cycle 14 on (b)(6) 2018.On (b)(6) 2018, computerized tomogram (ct scan) showed splenomegaly (15.3 cm) for the first time and more ascites than in previous ct scan but slight (free liquid in pelvis, no varices.The (b)(6) 2018, the subject experienced symptoms of edema ¼ grade 1 (mild), clinical ascites and related to hypoalbuminemia/portal hypertension (which was the first event to be noticed, the patient maintained good clinical condition with no signs of encephalopathy) and hence a gastroscopy was scheduled to evaluate presence of esophageal varices which would also reveal portal hypertension.On (b)(6) 2018, gastroscopy revealed large esophageal varices and antral gastropathy possibly secondary to portal hypertension.On (b)(6) 2018, the clinical ascites prompted to withdraw second line chemotherapy and required diuretics.The subject had eastern cooperative oncology group (ecog) performance status of 1 and also had diarrhea possibly due to viral infection.Paracentesis was not performed as ascites was not significant and there was no suspicion of peritoneal carcinomatosis.The subject was treated with diuretics.On (b)(6) 2018, the subject recovered from edema (which was g1 originally).On (b)(6) 2018, fibroscan/elastography performed did not confirmed fibrosis (f0-f1).On (b)(6) 2018, ct again confirmed splenomegaly - 15.3 cm which is stable since (b)(6) 2018.Liver parenchyma has appeared less heterogenous.(liver metastases are predominantly stable with some grow of the lesion in ii/iii segment) the scan confirmed reduced amount of free fluid - in the pelvis and abdomen.A cholelithiasis was reported.On (b)(6) 2018, the subjects hemodynamic study, done for the first time confirmed clinically significant sinusoidal portal hypertension.The liver biopsy (transjugular) was considered non conclusive, the sample size was insufficient, biopsy showed no steatosis.Percutaneous biopsy is planned for the subject.On (b)(6) 2018, the adverse event of symptomatic non-cirrhotic portal hypertension definitely related to sirt (therasphere®) resolved with sequelae.On (b)(6) 2018, the subject had improved albumin of 3.3 g/dl, no ascites and stable thrombocytopenia.The company assessed the event as possibly related to study device, second line chemotherapy (folfiri) and the role of the first line chemotherapy (folfox) regimen which is a drug known to provide sos liver damage is also to be considered.The complementary investigations reported the absence of fibrosis (elastometry) and a high gradient of pressure between the portal vein and sus hepatic vein (21 mmhg) while the normal is < 4.This confirms the portal hypertension by sinusoid blockage of non-cirrhotic origin (sos).Diagnosis of non-cirrhotic portal hypertension caused by therasphere® and possibly worsened by concomitant chemotherapy administration alongside with previous chemotherapy (first line (- folfox).Clinical presentation, endoscopy results, elastometry results, portal pressure measurements are concordant with this diagnosis.Liver biopsy was performed but inconclusive because the tissue sample was too small to conclude.The event was considered as not related to study procedure.For all other data please refer to the initial submission version of the report.A supplemental report will be submitted if additional relevant information is received.This case has been also reported as a usade associated with the ide.3 therasphere® vials were used to treat this patient, it cannot be determined which device contributed to this clinically significant event.Refer to mdr 3002124543-2018-00046 and 3002124543-2018-00048 for the other device associated with this event.
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