GELFOAM
Report
- Report Number
- 1810189-2024-00026
- Event Type
- Death
- Date Received
- July 23, 2024
- Date of Event
- November 1, 2023
- Report Date
- July 13, 2024
- Manufacturer
- PFIZER, INC.
- Product Code
- LMF
- PMA / PMN Number
- 18-286
- Adverse Event
- Yes
- Product Problem
- Yes
- Report Source
- Manufacturer report
- Reporter Location
- KS
- Reporter Occupation
- OTHER
- Health Professional
- N
Narratives
PRODUCT QUALITY GROUP PROVIDED INVESTIGATIONAL RESULTS ON 05SEP2024 FOR ABSORBABLE GELATIN: THE COMPLAINT FOR 'ADVERSE EVENT MD/MDCP' FOR AN UNKNOWN BATCH OF GELFOAM ABSORBABLE MATERIAL WAS INVESTIGATED. THE INVESTIGATION INCLUDED REVIEWING APRRS FOR THE PRODUCT AND A MEDICAL DEVICE TREND REVIEW. THE FINAL SCOPE WAS DETERMINED TO BE ALL BATCHES OF GELFOAM MANUFACTURED BY PFIZER KALAMAZOO WITHIN THE 36 MONTHS (THE EXPIRY INTERVAL OF THE PRODUCT) PRIOR TO THE RECEIPT DATE OF THE COMPLAINT. A COMPLAINT SAMPLE WAS NOT RETURNED. NO RELATED QUALITY ISSUES WERE IDENTIFIED DURING THE INVESTIGATION. NO ROOT CAUSE OR CAPA WERE IDENTIFIED AS THE COMPLAINT WAS NOT CONFIRMED. NO RELATED QUALITY DEFECTS WERE IDENTIFIED THROUGH INVESTIGATION. THERE IS NO IMPACT ON MEDICAL DEVICE QUALITY, REGULATORY, VALIDATION, OR STABILITY.
PRODUCT QUALITY GROUP PROVIDED INVESTIGATIONAL RESULTS ON (B)(6) 2024 FOR ABSORBABLE GELATIN: THE COMPLAINT FOR 'ADVERSE EVENT MD/MDCP' FOR AN UNKNOWN BATCH OF GELFOAM ABSORBABLE MATERIAL WAS INVESTIGATED. THE INVESTIGATION INCLUDED REVIEWING APRRS FOR THE PRODUCT AND A MEDICAL DEVICE TREND REVIEW. THE FINAL SCOPE WAS DETERMINED TO BE ALL BATCHES OF GELFOAM MANUFACTURED BY PFIZER KALAMAZOO WITHIN THE 36 MONTHS (THE EXPIRY INTERVAL OF THE PRODUCT) PRIOR TO THE RECEIPT DATE OF THE COMPLAINT. A COMPLAINT SAMPLE WAS NOT RETURNED. NO RELATED QUALITY ISSUES WERE IDENTIFIED DURING THE INVESTIGATION. NO ROOT CAUSE OR CAPA WERE IDENTIFIED AS THE COMPLAINT WAS NOT CONFIRMED. NO RELATED QUALITY DEFECTS WERE IDENTIFIED THROUGH INVESTIGATION. THERE IS NO IMPACT ON MEDICAL DEVICE QUALITY, REGULATORY, VALIDATION, OR STABILITY.
EVENT VERBATIM [PREFERRED TERM] EMERGENCY TRANSCATHETER HEMOSTASIS WAS PERFORMED/SELECTIVE EMBOLIZATION OF THESE VESSELS USING A GELATIN SPONGE [OFF LABEL USE], EMERGENCY TRANSCATHETER HEMOSTASIS WAS PERFORMED/SELECTIVE EMBOLIZATION OF THESE VESSELS USING A GELATIN SPONGE [DEVICE USE ISSUE], LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION [HEPATIC FAILURE], LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION [HEPATORENAL SYNDROME]. NARRATIVE: THIS IS A LITERATURE REPORT FROM PRODUCT QUALITY GROUP FOR THE FOLLOWING LITERATURE SOURCE(S): "FATAL INTRATUMORAL HEMORRHAGE IN A PATIENT WITH HEPATOCELLULAR CARCINOMA FOLLOWING SUCCESSFUL TREATMENT WITH ATEZOLIZUMAB/BEVACIZUMAB: A CASE REPORT", WORLD JOURNAL OF CLINICAL CASES, 2024; VOL:12 (22), PGS:5177-5183, DOI:10.12998/WJCC.V12.I22.5177. A 63-YEAR-OLD MALE PATIENT RECEIVED ABSORBABLE GELATIN (GELFOAM), SINCE NOV2023 FOR HAEMOSTASIS. THE PATIENT'S RELEVANT MEDICAL HISTORY INCLUDED: "ADVANCED HEPATOCELLULAR CARCINOMA", START DATE: APR2023 (UNSPECIFIED IF ONGOING); "EMERGENCY ROOM" (UNSPECIFIED IF ONGOING); "HEPATITIS C, GENOTYPE 1B", START DATE: 2017 (UNSPECIFIED IF ONGOING); "CIRRHOSIS", START DATE: APR2023 (UNSPECIFIED IF ONGOING); "MODERATE AMOUNT OF ASCITES" (UNSPECIFIED IF ONGOING). CONCOMITANT MEDICATION(S) INCLUDED: LIPIODOL TAKEN FOR EMBOLISM, START DATE: NOV2023. PAST DRUG HISTORY INCLUDED: 5-FU, START DATE: APR2023, STOP DATE: AUG2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "DISEASE PROGRESSION", NOTES: (500 MG/M^2) FOR 3 D EVERY 4 WK, 4 CYCLE; CISPLATIN, START DATE: APR2023, STOP DATE: AUG2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "DISEASE PROGRESSION", NOTES: (60 MG/M^2) FOR 3 D EVERY 4 WK, 4 CYCLE; TECENTRIQ, START DATE: AUG2023, STOP DATE: NOV2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "INTRATUMORAL HEMORRHAGE", NOTES: ATEZOLIZUMAB (TECENTRIQ 1200 MG PER DOSE; ROCHE INTERNATIONAL LLC., BASEL, SWITZERLAND); AVASTIN, START DATE: AUG2023, STOP DATE: NOV2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "INTRATUMORAL HEMORRHAGE", NOTES: BEVACIZUMAB (AVASTIN 15 MG/KG PER DOSE; GENENTECH, SOUTH SAN FRANCISCO, CA, UNITED STATES). THE FOLLOWING INFORMATION WAS REPORTED: OFF LABEL USE (DEATH), DEVICE USE ISSUE (DEATH) ALL WITH ONSET NOV2023, OUTCOME "FATAL" AND ALL DESCRIBED AS "EMERGENCY TRANSCATHETER HEMOSTASIS WAS PERFORMED/SELECTIVE EMBOLIZATION OF THESE VESSELS USING A GELATIN SPONGE"; HEPATIC FAILURE (DEATH), HEPATORENAL SYNDROME (DEATH) ALL WITH ONSET NOV2023, OUTCOME "FATAL" AND ALL DESCRIBED AS "LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION". THE PATIENT UNDERWENT THE FOLLOWING LABORATORY TESTS AND PROCEDURES: ALPHA 1 FOETOPROTEIN: (UNSPECIFIED DATE) INCREASING AFP LEVEL; ALPHA 1 FOETOPROTEIN: (UNSPECIFIED DATE) 2.5 NG/ML, NOTES: BASELINE; ANGIOGRAM: (UNSPECIFIED DATE) WAS PERFORMED FOR THE INTRATUMORAL PSEUDOANEURYSM,, NOTES: BUT EMBOLIZATION WAS NOT CONDUCTED AS THERE WAS NO EVIDENCE OF OVERT BLEEDING. THE PATIENT GENERAL CONDITION GRADUALLY IMPROVED; (UNSPECIFIED DATE) REVEALED ACTIVE CONTRAST EXTRAVASATION FROM THE S4, NOTES: TUMOR; BLOOD PRESSURE MEASUREMENT: (UNSPECIFIED DATE) 128/60 MMHG; BODY TEMPERATURE: (UNSPECIFIED DATE) 36.8 CENTIGRADE; CHILD-PUGH-TURCOTTE SCORE: (UNSPECIFIED DATE) 8; COMPUTERISED TOMOGRAM ABDOMEN: (UNSPECIFIED DATE) FOLLOWING THE THIRD CYCLE OF IMMUNOTHERAPY, THE, NOTES: TREATMENT RESPONSE WAS FORMALLY EVALUATED USING A CT SCAN. WE OBSERVED A DECREASE IN ARTERIAL ENHANCEMENT IN EXTENSIVE HCCS INVOLVING BOTH HEMILIVERS, AND THE TUMOR RESPONSE WAS EVALUATED AS A PARTIAL RESPONSE ACCORDING TO THE MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS CRITERIA; (UNSPECIFIED DATE) AFTER THE FOURTH CYCLE OF HEPATIC ARTERIAL, NOTES: INFUSION CHEMOTHERAPY, THE CT SCAN REVEALED PROGRESSION OF THE VIABLE TUMOR AT THE ANTERIOR ASPECT OF THE HCC AND OTHER EXTENSIVE HCCS INVOLVING BOTH LOBES OF THE LIVER ALONG WITH INCREASING AFP LEVELS; (UNSPECIFIED DATE) THE 3-PHASE COMPUTED TOMOGRAPHY (CT) REVEALED A, NOTES: A HEPATIC MASS, WITH THE LARGEST LESION LOCATED IN S4/8 MEASURING UP TO 11.7 CM AND INVOLVING METASTASIS TO THE T12 SPINE; (JUN2023) FOLLOWING THE SECOND CYCLE OF HEPATIC ARTERIAL, NOTES: INFUSION CHEMOTHERAPY, AN INTRATUMORAL PSEUDOANEURYSM MEASURING APPROXIMATELY 8 MM DEVELOPED AT THE ANTERIOR ASPECT OF THE NECROTIC HCC ON THE FOLLOW-UP CT, WHICH WAS NOT VISIBLE IN THE PREVIOUS SCAN; (AUG2023) SHOWED TUMOR PROGRESSION; (NOV2023) CONFIRMED THE COMPLETE HEMOSTASIS OF THE, NOTES: INTRATUMORAL HEMORRHAGE; (UNSPECIFIED DATE) REVEALED A FOCAL RUPTURE OF HCC IN THE MEDIAL, NOTES: SEGMENT INFERIOR PORTION (PREVIOUS INTRATUMORAL PSEUDOANEURYSM) WITH ACTIVE BLEEDING AND A LARGE AMOUNT OF HEMOPERITONEUM. ADDITIONALLY, MORE NECROSIS OF HCCS WAS OBSERVED IN BOTH LOBES; EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS: (UNSPECIFIED DATE) 1; HAEMOGLOBIN: (UNSPECIFIED DATE) 8.5 G/DL; HEART RATE: (UNSPECIFIED DATE) 58, NOTES: UNIT: BPM; INTERNATIONAL NORMALISED RATIO: (UNSPECIFIED DATE) 4.18; MODEL FOR END-STAGE LIVER DISEASE SCORE: (UNSPECIFIED DATE) 14; (UNSPECIFIED DATE) 8; LIVER FUNCTION TEST: (UNSPECIFIED DATE) REDUCED, NOTES: CATEGORIZED AS CHILD-PUGH CLASS B; (UNSPECIFIED DATE) THIRD HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE, NOTES: PATIENT LIVER FUNCTION IMPROVED TO CHILD-PUGH CLASS A (6), AND NO ASCITES WERE OBSERVED; (UNSPECIFIED DATE) GRADUALLY DETERIORATED; OESOPHAGOGASTRODUODENOSCOPY: (UNSPECIFIED DATE) MINIMAL ESOPHAGEAL VARICES WITHOUT RED COLOR SIGN, NOTES: WERE OBSERVED, AND GASTRIC VARICES WERE NOT PRESENT; PHYSICAL EXAMINATION: (UNSPECIFIED DATE) HIS VITAL SIGNS WERE GENERALLY NORMAL; PLATELET COUNT: (UNSPECIFIED DATE) 101 X10 3/MM3; RENAL FUNCTION TEST: (UNSPECIFIED DATE) WORSENING; RESPIRATORY RATE: (UNSPECIFIED DATE) 24, NOTES: UNIT: BREATHS PER MINUTE; WHITE BLOOD CELL COUNT: (UNSPECIFIED DATE) 17.78 X10 3/MM3. THE PATIENT DATE OF DEATH WAS NOV2023. REPORTED CAUSE OF DEATH: "LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION". IT WAS NOT REPORTED IF AN AUTOPSY WAS PERFORMED. THE REPORTER CONSIDERED "EMERGENCY TRANSCATHETER HEMOSTASIS WAS PERFORMED/SELECTIVE EMBOLIZATION OF THESE VESSELS USING A GELATIN SPONGE" AND "LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION" ASSOCIATED TO ABSORBABLE GELATIN. CAUSALITY FOR "EMERGENCY TRANSCATHETER HEMOSTASIS WAS PERFORMED/SELECTIVE EMBOLIZATION OF THESE VESSELS USING A GELATIN SPONGE" AND "LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION" WAS DETERMINED ASSOCIATED TO ABSORBABLE GELATIN (MALFUNCTION). CLINICAL COURSE: CASE SUMMARY: IN THIS CASE REPORT, WE PRESENT A RARE AND FATAL CASE OF INTRATUMORAL HEMORRHAGE IN A PATIENT WITH ADVANCED HCC FOLLOWING SUCCESSFUL TREATMENT WITH ATEZOLIZUMAB/ BEVACIZUMAB. A 63-YEAR-OLD MALE DIAGNOSED WITH HCC INITIALLY UNDERWENT FOUR CYCLES OF INTRA-ARTERIAL CHEMOTHERAPY. HOWEVER, FOLLOW-UP ABDOMINAL COMPUTED TOMOGRAPHY (CT) REVEALED DISEASE PROGRESSION. SUBSEQUENTLY, THE TREATMENT PLAN WAS MODIFIED TO ATEZOLIZUMAB/BEVACIZUMAB. AFTER THE FIFTH CYCLE OF ATEZOLIZUMAB/BEVACIZUMAB, CT SHOWED PARTIAL REGRESSION OF HCC. ONE WEEK LATER, HE VISITED THE EMERGENCY ROOM DUE TO SEVERE ABRUPT ABDOMINAL PAIN. ABDOMINAL CT REVEALED FOCAL RUPTURE OF HCC IN THE MEDIAL SEGMENT INFERIOR PORTION WITH ACTIVE BLEEDING AND A LARGE AMOUNT OF HEMOPERITONEUM. ANGIOGRAPHY WAS PERFORMED ON THE SAME DAY, AND EMBOLIZATION OF A4 AND A8 BRANCHES USING LIPIODOL AND GELFOAM WAS IMPLEMENTED. DESPITE SUCCESSFUL HEMOSTASIS, THE PATIENT SUBSEQUENTLY DEVELOPED LIVER FAILURE AND DIED. CONCLUSION: ATEZOLIZUMAB/BEVACIZUMAB FOR ADVANCED HCC SUGGESTS THAT INTRATUMORAL HEMORRHAGE MAY BE CRUCIAL DESPITE GOOD TUMOR RESPONSE AFTER IMMUNOTHERAPY, EMPHASIZING THE CONTINUOUS MONITORING OF THIS SIDE EFFECT. CHIEF COMPLAINTS: A PATIENT UNDERGOING TREATMENT WITH ATEZOLIZUMAB/BEVACIZUMAB FOR HEPATOCELLULAR CARCINOMA CAUSED BY CHRONIC HEPATITIS C PRESENTED TO THE EMERGENCY ROOM WITH SUDDEN ABDOMINAL PAIN. HISTORY OF PRESENT ILLNESS:A 63-YEAR-OLD MAN DIAGNOSED WITH HEPATITIS C, GENOTYPE 1B, AT A HOSPITAL IN CHINA IN 2017 UNDERWENT TREATMENT WITH A DIRECT-ACTING ANTIVIRAL AND HAD SINCE ACHIEVED A SUSTAINED VIROLOGIC RESPONSE. HOWEVER, THE PATIENT DID NOT VISIT THE HOSPITAL AFTER 2017, AND SURVEILLANCE TESTS FOR HCC WERE NOT PERFORMED. IN APRIL 2023, HE VISITED A HOSPITAL IN SOUTH KOREA WITH ABDOMINAL PAIN AND DISTENSION, AND WAS DIAGNOSED WITH ADVANCED HCC AND CIRRHOSIS. THE 3-PHASE COMPUTED TOMOGRAPHY (CT) REVEALED A HEPATIC MASS, WITH THE LARGEST LESION LOCATED IN S4/8 MEASURING UP TO 11.7 CM AND INVOLVING METASTASIS TO THE T12 SPINE. THE CANCER STAGE WAS MODIFIED UNION FOR INTERNATIONAL CANCER CONTROL STAGE IVB, T4N0M1, AND BARCELONA CLINIC LIVER CANCER STAGE D. THE BASELINE ALPHA-FETOPROTEIN (AFP) SERUM LEVEL WAS 2.5 NG/ML. THE UNDERLYING LIVER WAS ACCOMPANIED BY CIRRHOSIS AND A MODERATE AMOUNT OF ASCITES. LIVER FUNCTION HAD A CHILD-TURCOTTE-PUGH SCORE OF 8, AND THE MODEL FOR END-STAGE LIVER DISEASE SCORE WAS 14. IN EGD, MINIMAL ESOPHAGEAL VARICES WITHOUT RED COLOR SIGN WERE OBSERVED, AND GASTRIC VARICES WERE NOT PRESENT. THE EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS SCORE WAS 1. DUE TO THE PATIENT'S REDUCED LIVER FUNCTION, CATEGORIZED AS CHILD-PUGH CLASS B (8), SORAFENIB, LENVATINIB, OR ATEZOLIZUMAB/ BEVACIZUMAB WERE NOT COVERED BY THE NATIONAL INSURANCE SYSTEM IN SOUTH KOREA. CONSEQUENTLY, THE PATIENT UNDERWENT HEPATIC ARTERIAL INFUSION CHEMOTHERAPY USING 5-FU (500 MG/M^2) AND CISPLATIN (60 MG/M^2) FOR 3 D EVERY 4 WK. FOLLOWING THE SECOND CYCLE OF HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, AN INTRATUMORAL PSEUDOANEURYSM MEASURING APPROXIMATELY 8 MM DEVELOPED AT THE ANTERIOR ASPECT OF THE NECROTIC HCC ON THE FOLLOW-UP CT, WHICH WAS NOT VISIBLE IN THE PREVIOUS SCAN. ANGIOGRAPHY WAS PERFORMED FOR THE INTRATUMORAL PSEUDOANEURYSM, BUT EMBOLIZATION WAS NOT CONDUCTED AS THERE WAS NO EVIDENCE OF OVERT BLEEDING. THE PATIENT'S GENERAL CONDITION GRADUALLY IMPROVED. AFTER THE THIRD HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE PATIENT'S LIVER FUNCTION IMPROVED TO CHILD-PUGH CLASS A (6), AND NO ASCITES WERE OBSERVED. HOWEVER, AFTER THE FOURTH CYCLE OF HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE CT SCAN REVEALED PROGRESSION OF THE VIABLE TUMOR AT THE ANTERIOR ASPECT OF THE HCC AND OTHER EXTENSIVE HCCS INVOLVING BOTH LOBES OF THE LIVER, ALONG WITH INCREASING AFP LEVELS. AFTER THE FAILURE OF HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE PATIENT WAS STARTED ON ATEZOLIZUMAB/BEVACIZUMAB. ATEZOLIZUMAB (TECENTRIQ 1200 MG PER DOSE; ROCHE INTERNATIONAL LLC., BASEL, SWITZERLAND) AND BEVACIZUMAB (AVASTIN 15MG/KG PER DOSE; GENENTECH, SOUTH SAN FRANCISCO, CA, UNITED STATES) WERE ADMINISTERED EVERY 3 WK. FOLLOWING THE THIRD CYCLE OF IMMUNOTHERAPY, THE TREATMENT RESPONSE WAS FORMALLY EVALUATED USING A CT SCAN. WE OBSERVED A DECREASE IN ARTERIAL ENHANCEMENT IN EXTENSIVE HCCS INVOLVING BOTH HEMILIVERS, AND THE TUMOR RESPONSE WAS EVALUATED AS A PARTIAL RESPONSE ACCORDING TO THE MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS CRITERIA. SEVEN DAYS AFTER THE FIFTH CYCLE OF ATEZOLIZUMAB/BEVACIZUMAB, HE PRESENTED TO THE EMERGENCY ROOM DUE TO ABRUPT ABDOMINAL PAIN, RATED 8 ON THE NUMERICAL RATING SCALE. HISTORY OF PAST ILLNESS: APART FROM CHRONIC HEPATITIS C, THE PATIENT HAD NO SIGNIFICANT MEDICAL HISTORY. PERSONAL AND FAMILY HISTORY: THERE WAS NO FAMILY HISTORY OF ANY DISEASES OR CANCER. FINAL DIAGNOSIS: THE PATIENT WAS DIAGNOSED WITH AN INTRATUMORAL RUPTURE THAT OCCURRED DURING ATEZOLIZUMAB/BEVACIZUMAB TREATMENT FOR HCC. TREATMENT: EMERGENCY TRANSCATHETER HEMOSTASIS WAS PERFORMED DUE TO THE IDENTIFIED INTRATUMOR BLEEDING. ANGIOGRAPHY REVEALED ACTIVE CONTRAST EXTRAVASATION FROM THE S4 TUMOR. SELECTIVE EMBOLIZATION OF THESE VESSELS USING A GELATIN SPONGE AND LIPIODOL WAS PERFORMED. AFTER EMBOLIZATION, DYNAMIC CONTRAST-ENHANCED CT CONFIRMED THE COMPLETE HEMOSTASIS OF THE INTRATUMORAL HEMORRHAGE. OUTCOME AND FOLLOW-UP: DESPITE THE SUCCESSFUL EMBOLIZATION, THE PATIENT'S LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME DEVELOPED ON THE 10TH DAY AFTER EMBOLIZATION. THE PATIENT DIED 12 D AFTER EMBOLIZATION DUE TO THE WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION. DISCUSSION: THE PRIMARY CHALLENGE AT PRESENT IS THE ABSENCE OF IDENTIFIED PREVENTION OR TREATMENT STRATEGIES FOR THIS UNCOMMON INTRATUMORAL HEMORRHAGE. FOLLOWING THE SECOND HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, WE CONDUCTED ANGIOGRAPHY FOR PSEUDOANEURYSM; HOWEVER, EMBOLIZATION WAS NOT PERFORMED AS THERE WAS NO EVIDENCE OF BLEEDING. IN HINDSIGHT, EVEN IN THE ABSENCE OF APPARENT BLEEDING, PREVENTIVE EMBOLIZATION COULD HAVE BEEN CONSIDERED TO POTENTIALLY AVERT FATAL BLEEDING IN THE FUTURE. YET, THE EFFECTIVENESS OR SAFETY OF PROPHYLACTIC EMBOLIZATION FOR PSEUDOANEURYSM IN PATIENTS WITHOUT EVIDENCE OF INTRATUMORAL BLEEDING REMAINS UNDISCLOSED. IN SUMMARY, THIS CASE UNDERSCORES THE VARIED AND SOMETIMES FATAL BLEEDING COMPLICATIONS THAT CAN ARISE AFTER ATEZOLIZUMAB/BEVACIZUMAB TREATMENT IN PATIENTS WITH HEPATOCELLULAR CARCINOMA. PRODUCT QUALITY GROUP PROVIDED INVESTIGATIONAL RESULTS ON 05SEP2024 FOR ABSORBABLE GELATIN: THE COMPLAINT FOR 'ADVERSE EVENT MD/MDCP' FOR AN UNKNOWN BATCH OF GELFOAM ABSORBABLE MATERIAL WAS INVESTIGATED. THE INVESTIGATION INCLUDED REVIEWING APRRS FOR THE PRODUCT AND A MEDICAL DEVICE TREND REVIEW. THE FINAL SCOPE WAS DETERMINED TO BE ALL BATCHES OF GELFOAM MANUFACTURED BY PFIZER KALAMAZOO WITHIN THE 36 MONTHS (THE EXPIRY INTERVAL OF THE PRODUCT) PRIOR TO THE RECEIPT DATE OF THE COMPLAINT. A COMPLAINT SAMPLE WAS NOT RETURNED. NO RELATED QUALITY ISSUES WERE IDENTIFIED DURING THE INVESTIGATION. NO ROOT CAUSE OR CAPA WERE IDENTIFIED AS THE COMPLAINT WAS NOT CONFIRMED. NO RELATED QUALITY DEFECTS WERE IDENTIFIED THROUGH INVESTIGATION. THERE IS NO IMPACT ON MEDICAL DEVICE QUALITY, REGULATORY, VALIDATION, OR STABILITY. FOLLOW-UP (05SEP2024): THIS IS A FOLLOW-UP REPORT FROM PRODUCT QUALITY GROUP PROVIDING INVESTIGATION RESULTS. FOLLOW-UP (18NOV2024): THIS IS A FOLLOW-UP REPORT FROM PRODUCT QUALITY GROUP PROVIDING INVESTIGATION RESULTS. UPDATED INFORMATION INCLUDED: EVALUATION CODE AND EVENTS OFF LABEL USE AND DEVICE USE ISSUE ADDED., COMMENT: THE EVENTS HEPATIC FAILURE AND HEPATORENAL SYNDROME ARE ASSESSED AS SERIOUS, ASSOCIATED WITH THE PRODUCT ABSORBABLE GELATIN (GELFOAM) IN THE CONTEXT OF OFF LABEL USE FOR UNAPPROVED INDICATION, AND UNLISTED IN THE CDS OF THE PFIZER SUSPECT PRODUCT ABSORBABLE GELATIN. THIS CASE WILL BE REASSESSED WHEN ADDITIONAL INFORMATION IS RECEIVED. THE IMPACT OF THIS REPORT ON THE BENEFIT/RISK PROFILE OF THE PFIZER PRODUCT IS EVALUATED AS PART OF PFIZER PROCEDURES FOR SAFETY EVALUATION, INCLUDING THE REVIEW AND ANALYSIS OF AGGREGATE DATA FOR ADVERSE EVENTS. ANY SAFETY CONCERN IDENTIFIED AS PART OF THIS REVIEW, AS WELL AS ANY APPROPRIATE ACTION IN RESPONSE, WILL BE PROMPTLY NOTIFIED TO RAS, ETHICS COMMITTEES, AND INVESTIGATORS, AS APPROPRIATE.
EVENT VERBATIM [PREFERRED TERM] LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION [HEPATIC FAILURE], LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION [HEPATORENAL SYNDROME], , NARRATIVE: THIS IS A LITERATURE REPORT FOR THE FOLLOWING LITERATURE SOURCE(S): "FATAL INTRATUMORAL HEMORRHAGE IN A PATIENT WITH HEPATOCELLULAR CARCINOMA FOLLOWING SUCCESSFUL TREATMENT WITH ATEZOLIZUMAB/BEVACIZUMAB: A CASE REPORT", WORLD JOURNAL OF CLINICAL CASES, 2024; VOL:12 (22), PGS:5177-5183, DOI:10.12998/WJCC.V12.I22.5177. A 63-YEAR-OLD MALE PATIENT RECEIVED ABSORBABLE GELATIN (GELFOAM), SINCE NOV2023 FOR HAEMOSTASIS. THE PATIENT'S RELEVANT MEDICAL HISTORY INCLUDED: "ADVANCED HEPATOCELLULAR CARCINOMA", START DATE: APR2023 (UNSPECIFIED IF ONGOING); "EMERGENCY ROOM" (UNSPECIFIED IF ONGOING); "HEPATITIS C, GENOTYPE 1B", START DATE: 2017 (UNSPECIFIED IF ONGOING); "CIRRHOSIS", START DATE: APR2023 (UNSPECIFIED IF ONGOING); "MODERATE AMOUNT OF ASCITES" (UNSPECIFIED IF ONGOING). CONCOMITANT MEDICATION(S) INCLUDED: LIPIODOL TAKEN FOR EMBOLISM, START DATE: NOV2023. PAST DRUG HISTORY INCLUDED: 5-FU, START DATE: APR2023, STOP DATE: AUG2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "DISEASE PROGRESSION", NOTES: (500 MG/M^2) FOR 3 D EVERY 4 WK, 4 CYCLE; CISPLATIN, START DATE: APR2023, STOP DATE: AUG2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "DISEASE PROGRESSION", NOTES: (60 MG/M^2) FOR 3 D EVERY 4 WK, 4 CYCLE; TECENTRIQ, START DATE: AUG2023, STOP DATE: NOV2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "INTRATUMORAL HEMORRHAGE", NOTES: ATEZOLIZUMAB (TECENTRIQ 1200 MG PER DOSE; ROCHE INTERNATIONAL LLC., BASEL, SWITZERLAND); AVASTIN, START DATE: AUG2023, STOP DATE: NOV2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "INTRATUMORAL HEMORRHAGE", NOTES: BEVACIZUMAB (AVASTIN 15 MG/KG PER DOSE; GENENTECH, SOUTH SAN FRANCISCO, CA, UNITED STATES). THE FOLLOWING INFORMATION WAS REPORTED: HEPATIC FAILURE (DEATH), HEPATORENAL SYNDROME (DEATH) ALL WITH ONSET NOV2023, OUTCOME "FATAL" AND ALL DESCRIBED AS "LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION". THE PATIENT UNDERWENT THE FOLLOWING LABORATORY TESTS AND PROCEDURES: ALPHA 1 FOETOPROTEIN: (UNSPECIFIED DATE) INCREASING AFP LEVEL; ALPHA 1 FOETOPROTEIN: (UNSPECIFIED DATE) 2.5 NG/ML, NOTES: BASELINE; ANGIOGRAM: (UNSPECIFIED DATE) WAS PERFORMED FOR THE INTRATUMORAL PSEUDOANEURYSM,, NOTES: BUT EMBOLIZATION WAS NOT CONDUCTED AS THERE WAS NO EVIDENCE OF OVERT BLEEDING. THE PATIENT GENERAL CONDITION GRADUALLY IMPROVED; (UNSPECIFIED DATE) REVEALED ACTIVE CONTRAST EXTRAVASATION FROM THE S4, NOTES: TUMOR; BLOOD PRESSURE MEASUREMENT: (UNSPECIFIED DATE) 128/60 MMHG; BODY TEMPERATURE: (UNSPECIFIED DATE) 36.8 CENTIGRADE; CHILD-PUGH-TURCOTTE SCORE: (UNSPECIFIED DATE) 8; COMPUTERISED TOMOGRAM ABDOMEN: (UNSPECIFIED DATE) FOLLOWING THE THIRD CYCLE OF IMMUNOTHERAPY, THE, NOTES: TREATMENT RESPONSE WAS FORMALLY EVALUATED USING A CT SCAN. WE OBSERVED A DECREASE IN ARTERIAL ENHANCEMENT IN EXTENSIVE HCCS INVOLVING BOTH HEMILIVERS, AND THE TUMOR RESPONSE WAS EVALUATED AS A PARTIAL RESPONSE ACCORDING TO THE MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS CRITERIA; (UNSPECIFIED DATE) AFTER THE FOURTH CYCLE OF HEPATIC ARTERIAL, NOTES: INFUSION CHEMOTHERAPY, THE CT SCAN REVEALED PROGRESSION OF THE VIABLE TUMOR AT THE ANTERIOR ASPECT OF THE HCC AND OTHER EXTENSIVE HCCS INVOLVING BOTH LOBES OF THE LIVER ALONG WITH INCREASING AFP LEVELS; (UNSPECIFIED DATE) THE 3-PHASE COMPUTED TOMOGRAPHY (CT) REVEALED A, NOTES: A HEPATIC MASS, WITH THE LARGEST LESION LOCATED IN S4/8 MEASURING UP TO 11.7 CM AND INVOLVING METASTASIS TO THE T12 SPINE; (JUN2023) FOLLOWING THE SECOND CYCLE OF HEPATIC ARTERIAL, NOTES: INFUSION CHEMOTHERAPY, AN INTRATUMORAL PSEUDOANEURYSM MEASURING APPROXIMATELY 8 MM DEVELOPED AT THE ANTERIOR ASPECT OF THE NECROTIC HCC ON THE FOLLOW-UP CT, WHICH WAS NOT VISIBLE IN THE PREVIOUS SCAN; (AUG2023) SHOWED TUMOR PROGRESSION; (NOV2023) CONFIRMED THE COMPLETE HEMOSTASIS OF THE, NOTES: INTRATUMORAL HEMORRHAGE; (UNSPECIFIED DATE) REVEALED A FOCAL RUPTURE OF HCC IN THE MEDIAL, NOTES: SEGMENT INFERIOR PORTION (PREVIOUS INTRATUMORAL PSEUDOANEURYSM) WITH ACTIVE BLEEDING AND A LARGE AMOUNT OF HEMOPERITONEUM. ADDITIONALLY, MORE NECROSIS OF HCCS WAS OBSERVED IN BOTH LOBES; EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS: (UNSPECIFIED DATE) 1; HAEMOGLOBIN: (UNSPECIFIED DATE) 8.5 G/DL; HEART RATE: (UNSPECIFIED DATE) 58, NOTES: UNIT: BPM; INTERNATIONAL NORMALISED RATIO: (UNSPECIFIED DATE) 4.18; MODEL FOR END-STAGE LIVER DISEASE SCORE: (UNSPECIFIED DATE) 14; (UNSPECIFIED DATE) 8; LIVER FUNCTION TEST: (UNSPECIFIED DATE) REDUCED, NOTES: CATEGORIZED AS CHILD-PUGH CLASS B; (UNSPECIFIED DATE) THIRD HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE, NOTES: PATIENT LIVER FUNCTION IMPROVED TO CHILD-PUGH CLASS A (6), AND NO ASCITES WERE OBSERVED; (UNSPECIFIED DATE) GRADUALLY DETERIORATED; OESOPHAGOGASTRODUODENOSCOPY: (UNSPECIFIED DATE) MINIMAL ESOPHAGEAL VARICES WITHOUT RED COLOR SIGN, NOTES: WERE OBSERVED, AND GASTRIC VARICES WERE NOT PRESENT; PHYSICAL EXAMINATION: (UNSPECIFIED DATE) HIS VITAL SIGNS WERE GENERALLY NORMAL; PLATELET COUNT: (UNSPECIFIED DATE) 101 X10 3/MM3; RENAL FUNCTION TEST: (UNSPECIFIED DATE) WORSENING; RESPIRATORY RATE: (UNSPECIFIED DATE) 24, NOTES: UNIT: BREATHS PER MINUTE; WHITE BLOOD CELL COUNT: (UNSPECIFIED DATE) 17.78 X10 3/MM3. THE PATIENT DATE OF DEATH WAS (B)(6) 2023. REPORTED CAUSE OF DEATH: "LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION". IT WAS NOT REPORTED IF AN AUTOPSY WAS PERFORMED. CAUSALITY FOR "LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION" WAS DETERMINED ASSOCIATED TO ABSORBABLE GELATIN (MALFUNCTION). CLINICAL COURSE: CASE SUMMARY: IN THIS CASE REPORT, WE PRESENT A RARE AND FATAL CASE OF INTRATUMORAL HEMORRHAGE IN A PATIENT WITH ADVANCED HCC FOLLOWING SUCCESSFUL TREATMENT WITH ATEZOLIZUMAB/ BEVACIZUMAB. A 63-YEAR-OLD MALE DIAGNOSED WITH HCC INITIALLY UNDERWENT FOUR CYCLES OF INTRA-ARTERIAL CHEMOTHERAPY. HOWEVER, FOLLOW-UP ABDOMINAL COMPUTED TOMOGRAPHY (CT) REVEALED DISEASE PROGRESSION. SUBSEQUENTLY, THE TREATMENT PLAN WAS MODIFIED TO ATEZOLIZUMAB/BEVACIZUMAB. AFTER THE FIFTH CYCLE OF ATEZOLIZUMAB/BEVACIZUMAB, CT SHOWED PARTIAL REGRESSION OF HCC. ONE WEEK LATER, HE VISITED THE EMERGENCY ROOM DUE TO SEVERE ABRUPT ABDOMINAL PAIN. ABDOMINAL CT REVEALED FOCAL RUPTURE OF HCC IN THE MEDIAL SEGMENT INFERIOR PORTION WITH ACTIVE BLEEDING AND A LARGE AMOUNT OF HEMOPERITONEUM. ANGIOGRAPHY WAS PERFORMED ON THE SAME DAY, AND EMBOLIZATION OF A4 AND A8 BRANCHES USING LIPIODOL AND GELFOAM WAS IMPLEMENTED. DESPITE SUCCESSFUL HEMOSTASIS, THE PATIENT SUBSEQUENTLY DEVELOPED LIVER FAILURE AND DIED. CONCLUSION: ATEZOLIZUMAB/BEVACIZUMAB FOR ADVANCED HCC SUGGESTS THAT INTRATUMORAL HEMORRHAGE MAY BE CRUCIAL DESPITE GOOD TUMOR RESPONSE AFTER IMMUNOTHERAPY, EMPHASIZING THE CONTINUOUS MONITORING OF THIS SIDE EFFECT. CHIEF COMPLAINTS: A PATIENT UNDERGOING TREATMENT WITH ATEZOLIZUMAB/BEVACIZUMAB FOR HEPATOCELLULAR CARCINOMA CAUSED BY CHRONIC HEPATITIS C PRESENTED TO THE EMERGENCY ROOM WITH SUDDEN ABDOMINAL PAIN. HISTORY OF PRESENT ILLNESS:A 63-YEAR-OLD MAN DIAGNOSED WITH HEPATITIS C, GENOTYPE 1B, AT A HOSPITAL IN CHINA IN 2017 UNDERWENT TREATMENT WITH A DIRECT-ACTING ANTIVIRAL AND HAD SINCE ACHIEVED A SUSTAINED VIROLOGIC RESPONSE. HOWEVER, THE PATIENT DID NOT VISIT THE HOSPITAL AFTER 2017, AND SURVEILLANCE TESTS FOR HCC WERE NOT PERFORMED. IN APRIL 2023, HE VISITED A HOSPITAL IN SOUTH KOREA WITH ABDOMINAL PAIN AND DISTENSION, AND WAS DIAGNOSED WITH ADVANCED HCC AND CIRRHOSIS. THE 3-PHASE COMPUTED TOMOGRAPHY (CT) REVEALED A HEPATIC MASS, WITH THE LARGEST LESION LOCATED IN S4/8 MEASURING UP TO 11.7 CM AND INVOLVING METASTASIS TO THE T12 SPINE. THE CANCER STAGE WAS MODIFIED UNION FOR INTERNATIONAL CANCER CONTROL STAGE IVB, T4N0M1, AND BARCELONA CLINIC LIVER CANCER STAGE D. THE BASELINE ALPHA-FETOPROTEIN (AFP) SERUM LEVEL WAS 2.5 NG/ML. THE UNDERLYING LIVER WAS ACCOMPANIED BY CIRRHOSIS AND A MODERATE AMOUNT OF ASCITES. LIVER FUNCTION HAD A CHILD-TURCOTTE-PUGH SCORE OF 8, AND THE MODEL FOR END-STAGE LIVER DISEASE SCORE WAS 14. IN EGD, MINIMAL ESOPHAGEAL VARICES WITHOUT RED COLOR SIGN WERE OBSERVED, AND GASTRIC VARICES WERE NOT PRESENT. THE EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS SCORE WAS 1. DUE TO THE PATIENT'S REDUCED LIVER FUNCTION, CATEGORIZED AS CHILD-PUGH CLASS B (8), SORAFENIB, LENVATINIB, OR ATEZOLIZUMAB/ BEVACIZUMAB WERE NOT COVERED BY THE NATIONAL INSURANCE SYSTEM IN SOUTH KOREA. CONSEQUENTLY, THE PATIENT UNDERWENT HEPATIC ARTERIAL INFUSION CHEMOTHERAPY USING 5-FU (500 MG/M^2) AND CISPLATIN (60 MG/M^2) FOR 3 D EVERY 4 WK. FOLLOWING THE SECOND CYCLE OF HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, AN INTRATUMORAL PSEUDOANEURYSM MEASURING APPROXIMATELY 8 MM DEVELOPED AT THE ANTERIOR ASPECT OF THE NECROTIC HCC ON THE FOLLOW-UP CT, WHICH WAS NOT VISIBLE IN THE PREVIOUS SCAN. ANGIOGRAPHY WAS PERFORMED FOR THE INTRATUMORAL PSEUDOANEURYSM, BUT EMBOLIZATION WAS NOT CONDUCTED AS THERE WAS NO EVIDENCE OF OVERT BLEEDING. THE PATIENT'S GENERAL CONDITION GRADUALLY IMPROVED. AFTER THE THIRD HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE PATIENT'S LIVER FUNCTION IMPROVED TO CHILD-PUGH CLASS A (6), AND NO ASCITES WERE OBSERVED. HOWEVER, AFTER THE FOURTH CYCLE OF HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE CT SCAN REVEALED PROGRESSION OF THE VIABLE TUMOR AT THE ANTERIOR ASPECT OF THE HCC AND OTHER EXTENSIVE HCCS INVOLVING BOTH LOBES OF THE LIVER, ALONG WITH INCREASING AFP LEVELS. AFTER THE FAILURE OF HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE PATIENT WAS STARTED ON ATEZOLIZUMAB/BEVACIZUMAB. ATEZOLIZUMAB (TECENTRIQ 1200 MG PER DOSE; ROCHE INTERNATIONAL LLC., BASEL, SWITZERLAND) AND BEVACIZUMAB (AVASTIN 15MG/KG PER DOSE; GENENTECH, SOUTH SAN FRANCISCO, CA, UNITED STATES) WERE ADMINISTERED EVERY 3 WK. FOLLOWING THE THIRD CYCLE OF IMMUNOTHERAPY, THE TREATMENT RESPONSE WAS FORMALLY EVALUATED USING A CT SCAN. WE OBSERVED A DECREASE IN ARTERIAL ENHANCEMENT IN EXTENSIVE HCCS INVOLVING BOTH HEMILIVERS, AND THE TUMOR RESPONSE WAS EVALUATED AS A PARTIAL RESPONSE ACCORDING TO THE MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS CRITERIA. SEVEN DAYS AFTER THE FIFTH CYCLE OF ATEZOLIZUMAB/BEVACIZUMAB, HE PRESENTED TO THE EMERGENCY ROOM DUE TO ABRUPT ABDOMINAL PAIN, RATED 8 ON THE NUMERICAL RATING SCALE. HISTORY OF PAST ILLNESS: APART FROM CHRONIC HEPATITIS C, THE PATIENT HAD NO SIGNIFICANT MEDICAL HISTORY. PERSONAL AND FAMILY HISTORY: THERE WAS NO FAMILY HISTORY OF ANY DISEASES OR CANCER. FINAL DIAGNOSIS: THE PATIENT WAS DIAGNOSED WITH AN INTRATUMORAL RUPTURE THAT OCCURRED DURING ATEZOLIZUMAB/BEVACIZUMAB TREATMENT FOR HCC. TREATMENT: EMERGENCY TRANSCATHETER HEMOSTASIS WAS PERFORMED DUE TO THE IDENTIFIED INTRATUMOR BLEEDING. ANGIOGRAPHY REVEALED ACTIVE CONTRAST EXTRAVASATION FROM THE S4 TUMOR. SELECTIVE EMBOLIZATION OF THESE VESSELS USING A GELATIN SPONGE AND LIPIODOL WAS PERFORMED. AFTER EMBOLIZATION, DYNAMIC CONTRAST-ENHANCED CT CONFIRMED THE COMPLETE HEMOSTASIS OF THE INTRATUMORAL HEMORRHAGE. OUTCOME AND FOLLOW-UP: DESPITE THE SUCCESSFUL EMBOLIZATION, THE PATIENT'S LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME DEVELOPED ON THE 10TH DAY AFTER EMBOLIZATION. THE PATIENT DIED 12 D AFTER EMBOLIZATION DUE TO THE WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION. DISCUSSION: THE PRIMARY CHALLENGE AT PRESENT IS THE ABSENCE OF IDENTIFIED PREVENTION OR TREATMENT STRATEGIES FOR THIS UNCOMMON INTRATUMORAL HEMORRHAGE. FOLLOWING THE SECOND HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, WE CONDUCTED ANGIOGRAPHY FOR PSEUDOANEURYSM; HOWEVER, EMBOLIZATION WAS NOT PERFORMED AS THERE WAS NO EVIDENCE OF BLEEDING. IN HINDSIGHT, EVEN IN THE ABSENCE OF APPARENT BLEEDING, PREVENTIVE EMBOLIZATION COULD HAVE BEEN CONSIDERED TO POTENTIALLY AVERT FATAL BLEEDING IN THE FUTURE. YET, THE EFFECTIVENESS OR SAFETY OF PROPHYLACTIC EMBOLIZATION FOR PSEUDOANEURYSM IN PATIENTS WITHOUT EVIDENCE OF INTRATUMORAL BLEEDING REMAINS UNDISCLOSED. IN SUMMARY, THIS CASE UNDERSCORES THE VARIED AND SOMETIMES FATAL BLEEDING COMPLICATIONS THAT CAN ARISE AFTER ATEZOLIZUMAB/BEVACIZUMAB TREATMENT IN PATIENTS WITH HEPATOCELLULAR CARCINOMA., COMMENT: THE EVENTS HEPATIC FAILURE AND HEPATORENAL SYNDROME ARE ASSESSED AS SERIOUS, ASSOCIATED WITH THE PRODUCT ABSORBABLE GELATIN (GELFOAM), AND UNLISTED IN THE CDS OF THE PFIZER SUSPECT PRODUCT ABSORBABLE GELATIN. THIS CASE WILL BE REASSESSED WHEN ADDITIONAL INFORMATION IS RECEIVED.
EVENT VERBATIM [PREFERRED TERM] LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION [HEPATIC FAILURE], LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION [HEPATORENAL SYNDROME], , NARRATIVE: THIS IS A LITERATURE REPORT FROM PRODUCT QUALITY GROUP FOR THE FOLLOWING LITERATURE SOURCE(S): "FATAL INTRATUMORAL HEMORRHAGE IN A PATIENT WITH HEPATOCELLULAR CARCINOMA FOLLOWING SUCCESSFUL TREATMENT WITH ATEZOLIZUMAB/BEVACIZUMAB: A CASE REPORT", WORLD JOURNAL OF CLINICAL CASES, 2024; VOL:12 (22), PGS:5177-5183, DOI:10.12998/WJCC.V12.I22.5177. A 63-YEAR-OLD MALE PATIENT RECEIVED ABSORBABLE GELATIN (GELFOAM), SINCE (B)(6) 2023 FOR HAEMOSTASIS. THE PATIENT'S RELEVANT MEDICAL HISTORY INCLUDED: "ADVANCED HEPATOCELLULAR CARCINOMA", START DATE: (B)(6) 2023 (UNSPECIFIED IF ONGOING); "EMERGENCY ROOM" (UNSPECIFIED IF ONGOING); "HEPATITIS C, GENOTYPE 1B", START DATE: 2017 (UNSPECIFIED IF ONGOING); "CIRRHOSIS", START DATE: (B)(6) 2023 (UNSPECIFIED IF ONGOING); "MODERATE AMOUNT OF ASCITES" (UNSPECIFIED IF ONGOING). CONCOMITANT MEDICATION(S) INCLUDED: LIPIODOL TAKEN FOR EMBOLISM, START DATE: (B)(6) 2023. PAST DRUG HISTORY INCLUDED: 5-FU, START DATE: (B)(6) 2023, STOP DATE: (B)(6) 2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "DISEASE PROGRESSION", NOTES: (500 MG/M^2) FOR 3 D EVERY 4 WK, 4 CYCLE; CISPLATIN, START DATE:(B)(6) 2023, STOP DATE:(B)(6) 2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "DISEASE PROGRESSION", NOTES: (60 MG/M^2) FOR 3 D EVERY 4 WK, 4 CYCLE; TECENTRIQ, START DATE: (B)(6) 2023, STOP DATE: (B)(6) 2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "INTRATUMORAL HEMORRHAGE", NOTES: ATEZOLIZUMAB (TECENTRIQ 1200 MG PER DOSE; ROCHE INTERNATIONAL LLC., (B)(6), SWITZERLAND); AVASTIN, START DATE: (B)(6) 2023, STOP DATE: (B)(6) 2023, FOR ADVANCED HEPATOCELLULAR CARCINOMA, REACTION(S): "INTRATUMORAL HEMORRHAGE", NOTES: BEVACIZUMAB (AVASTIN 15 MG/KG PER DOSE; GENENTECH, (B)(6), CA, UNITED STATES). THE FOLLOWING INFORMATION WAS REPORTED: HEPATIC FAILURE (DEATH), HEPATORENAL SYNDROME (DEATH) ALL WITH ONSET (B)(6) 2023, OUTCOME "FATAL" AND ALL DESCRIBED AS "LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION". THE PATIENT UNDERWENT THE FOLLOWING LABORATORY TESTS AND PROCEDURES: ALPHA 1 FOETOPROTEIN: (UNSPECIFIED DATE) INCREASING AFP LEVEL; ALPHA 1 FOETOPROTEIN: (UNSPECIFIED DATE) 2.5 NG/ML, NOTES: BASELINE; ANGIOGRAM: (UNSPECIFIED DATE) WAS PERFORMED FOR THE INTRATUMORAL PSEUDOANEURYSM. NOTES: BUT EMBOLIZATION WAS NOT CONDUCTED AS THERE WAS NO EVIDENCE OF OVERT BLEEDING. THE PATIENT GENERAL CONDITION GRADUALLY IMPROVED; (UNSPECIFIED DATE) REVEALED ACTIVE CONTRAST EXTRAVASATION FROM THE S4, NOTES: TUMOR; BLOOD PRESSURE MEASUREMENT: (UNSPECIFIED DATE) 128/60 MMHG; BODY TEMPERATURE: (UNSPECIFIED DATE) 36.8 CENTIGRADE; CHILD-PUGH-TURCOTTE SCORE: (UNSPECIFIED DATE) 8; COMPUTERISED TOMOGRAM ABDOMEN: (UNSPECIFIED DATE) FOLLOWING THE THIRD CYCLE OF IMMUNOTHERAPY, THE, NOTES: TREATMENT RESPONSE WAS FORMALLY EVALUATED USING A CT SCAN. WE OBSERVED A DECREASE IN ARTERIAL ENHANCEMENT IN EXTENSIVE HCCS INVOLVING BOTH HEMILIVERS, AND THE TUMOR RESPONSE WAS EVALUATED AS A PARTIAL RESPONSE ACCORDING TO THE MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS CRITERIA; (UNSPECIFIED DATE) AFTER THE FOURTH CYCLE OF HEPATIC ARTERIAL, NOTES: INFUSION CHEMOTHERAPY, THE CT SCAN REVEALED PROGRESSION OF THE VIABLE TUMOR AT THE ANTERIOR ASPECT OF THE HCC AND OTHER EXTENSIVE HCCS INVOLVING BOTH LOBES OF THE LIVER ALONG WITH INCREASING AFP LEVELS; (UNSPECIFIED DATE) THE 3-PHASE COMPUTED TOMOGRAPHY (CT) REVEALED A, NOTES: A HEPATIC MASS, WITH THE LARGEST LESION LOCATED IN S4/8 MEASURING UP TO 11.7 CM AND INVOLVING METASTASIS TO THE T12 SPINE; ((B)(6) 2023) FOLLOWING THE SECOND CYCLE OF HEPATIC ARTERIAL, NOTES: INFUSION CHEMOTHERAPY, AN INTRATUMORAL PSEUDOANEURYSM MEASURING APPROXIMATELY 8 MM DEVELOPED AT THE ANTERIOR ASPECT OF THE NECROTIC HCC ON THE FOLLOW-UP CT, WHICH WAS NOT VISIBLE IN THE PREVIOUS SCAN; ((B)(6) 2023) SHOWED TUMOR PROGRESSION; ((B)(6) 2023) CONFIRMED THE COMPLETE HEMOSTASIS OF THE, NOTES: INTRATUMORAL HEMORRHAGE; (UNSPECIFIED DATE) REVEALED A FOCAL RUPTURE OF HCC IN THE MEDIAL, NOTES: SEGMENT INFERIOR PORTION (PREVIOUS INTRATUMORAL PSEUDOANEURYSM) WITH ACTIVE BLEEDING AND A LARGE AMOUNT OF HEMOPERITONEUM. ADDITIONALLY, MORE NECROSIS OF HCCS WAS OBSERVED IN BOTH LOBES; EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS: (UNSPECIFIED DATE) 1; HAEMOGLOBIN: (UNSPECIFIED DATE) 8.5 G/DL; HEART RATE: (UNSPECIFIED DATE) 58, NOTES: UNIT: BPM; INTERNATIONAL NORMALISED RATIO: (UNSPECIFIED DATE) 4.18; MODEL FOR END-STAGE LIVER DISEASE SCORE: (UNSPECIFIED DATE) 14; (UNSPECIFIED DATE) 8; LIVER FUNCTION TEST: (UNSPECIFIED DATE) REDUCED, NOTES: CATEGORIZED AS CHILD-PUGH CLASS B; (UNSPECIFIED DATE) THIRD HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE, NOTES: PATIENT LIVER FUNCTION IMPROVED TO CHILD-PUGH CLASS A (6), AND NO ASCITES WERE OBSERVED; (UNSPECIFIED DATE) GRADUALLY DETERIORATED; OESOPHAGOGASTRODUODENOSCOPY: (UNSPECIFIED DATE) MINIMAL ESOPHAGEAL VARICES WITHOUT RED COLOR SIGN, NOTES: WERE OBSERVED, AND GASTRIC VARICES WERE NOT PRESENT; PHYSICAL EXAMINATION: (UNSPECIFIED DATE) HIS VITAL SIGNS WERE GENERALLY NORMAL; PLATELET COUNT: (UNSPECIFIED DATE) 101 X10 3/MM3; RENAL FUNCTION TEST: (UNSPECIFIED DATE) WORSENING; RESPIRATORY RATE: (UNSPECIFIED DATE) 24, NOTES: UNIT: BREATHS PER MINUTE; WHITE BLOOD CELL COUNT: (UNSPECIFIED DATE) 17.78 X10 3/MM3. THE PATIENT DATE OF DEATH WAS (B)(6) 2023. REPORTED CAUSE OF DEATH: "LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION". IT WAS NOT REPORTED IF AN AUTOPSY WAS PERFORMED. CAUSALITY FOR "LIVER FAILURE/LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME/ WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION" WAS DETERMINED ASSOCIATED TO ABSORBABLE GELATIN (MALFUNCTION). CLINICAL COURSE: CASE SUMMARY: IN THIS CASE REPORT, WE PRESENT A RARE AND FATAL CASE OF INTRATUMORAL HEMORRHAGE IN A PATIENT WITH ADVANCED HCC FOLLOWING SUCCESSFUL TREATMENT WITH ATEZOLIZUMAB/ BEVACIZUMAB. A 63-YEAR-OLD MALE DIAGNOSED WITH HCC INITIALLY UNDERWENT FOUR CYCLES OF INTRA-ARTERIAL CHEMOTHERAPY. HOWEVER, FOLLOW-UP ABDOMINAL COMPUTED TOMOGRAPHY (CT) REVEALED DISEASE PROGRESSION. SUBSEQUENTLY, THE TREATMENT PLAN WAS MODIFIED TO ATEZOLIZUMAB/BEVACIZUMAB. AFTER THE FIFTH CYCLE OF ATEZOLIZUMAB/BEVACIZUMAB, CT SHOWED PARTIAL REGRESSION OF HCC. ONE WEEK LATER, HE VISITED THE EMERGENCY ROOM DUE TO SEVERE ABRUPT ABDOMINAL PAIN. ABDOMINAL CT REVEALED FOCAL RUPTURE OF HCC IN THE MEDIAL SEGMENT INFERIOR PORTION WITH ACTIVE BLEEDING AND A LARGE AMOUNT OF HEMOPERITONEUM. ANGIOGRAPHY WAS PERFORMED ON THE SAME DAY, AND EMBOLIZATION OF A4 AND A8 BRANCHES USING LIPIODOL AND GELFOAM WAS IMPLEMENTED. DESPITE SUCCESSFUL HEMOSTASIS, THE PATIENT SUBSEQUENTLY DEVELOPED LIVER FAILURE AND DIED. CONCLUSION: ATEZOLIZUMAB/BEVACIZUMAB FOR ADVANCED HCC SUGGESTS THAT INTRATUMORAL HEMORRHAGE MAY BE CRUCIAL DESPITE GOOD TUMOR RESPONSE AFTER IMMUNOTHERAPY, EMPHASIZING THE CONTINUOUS MONITORING OF THIS SIDE EFFECT. CHIEF COMPLAINTS: A PATIENT UNDERGOING TREATMENT WITH ATEZOLIZUMAB/BEVACIZUMAB FOR HEPATOCELLULAR CARCINOMA CAUSED BY CHRONIC HEPATITIS C PRESENTED TO THE EMERGENCY ROOM WITH SUDDEN ABDOMINAL PAIN. HISTORY OF PRESENT ILLNESS: A 63-YEAR-OLD MAN DIAGNOSED WITH HEPATITIS C, GENOTYPE 1B, AT A HOSPITAL IN CHINA IN 2017 UNDERWENT TREATMENT WITH A DIRECT-ACTING ANTIVIRAL AND HAD SINCE ACHIEVED A SUSTAINED VIROLOGIC RESPONSE. HOWEVER, THE PATIENT DID NOT VISIT THE HOSPITAL AFTER 2017, AND SURVEILLANCE TESTS FOR HCC WERE NOT PERFORMED. IN (B)(6) 2023, HE VISITED A HOSPITAL IN SOUTH KOREA WITH ABDOMINAL PAIN AND DISTENSION AND WAS DIAGNOSED WITH ADVANCED HCC AND CIRRHOSIS. THE 3-PHASE COMPUTED TOMOGRAPHY (CT) REVEALED A HEPATIC MASS, WITH THE LARGEST LESION LOCATED IN S4/8 MEASURING UP TO 11.7 CM AND INVOLVING METASTASIS TO THE T12 SPINE. THE CANCER STAGE WAS MODIFIED UNION FOR INTERNATIONAL CANCER CONTROL STAGE IVB, T4N0M1, AND (B)(6) CLINIC LIVER CANCER STAGE D. THE BASELINE ALPHA-FETOPROTEIN (AFP) SERUM LEVEL WAS 2.5 NG/ML. THE UNDERLYING LIVER WAS ACCOMPANIED BY CIRRHOSIS AND A MODERATE AMOUNT OF ASCITES. LIVER FUNCTION HAD A CHILD-TURCOTTE-PUGH SCORE OF 8, AND THE MODEL FOR END-STAGE LIVER DISEASE SCORE WAS 14. IN EGD, MINIMAL ESOPHAGEAL VARICES WITHOUT RED COLOR SIGN WERE OBSERVED, AND GASTRIC VARICES WERE NOT PRESENT. THE EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS SCORE WAS 1. DUE TO THE PATIENT'S REDUCED LIVER FUNCTION, CATEGORIZED AS CHILD-PUGH CLASS B (8), SORAFENIB, LENVATINIB, OR ATEZOLIZUMAB/ BEVACIZUMAB WERE NOT COVERED BY THE NATIONAL INSURANCE SYSTEM IN SOUTH KOREA. CONSEQUENTLY, THE PATIENT UNDERWENT HEPATIC ARTERIAL INFUSION CHEMOTHERAPY USING 5-FU (500 MG/M^2) AND CISPLATIN (60 MG/M^2) FOR 3 D EVERY 4 WK. FOLLOWING THE SECOND CYCLE OF HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, AN INTRATUMORAL PSEUDOANEURYSM MEASURING APPROXIMATELY 8 MM DEVELOPED AT THE ANTERIOR ASPECT OF THE NECROTIC HCC ON THE FOLLOW-UP CT, WHICH WAS NOT VISIBLE IN THE PREVIOUS SCAN. ANGIOGRAPHY WAS PERFORMED FOR THE INTRATUMORAL PSEUDOANEURYSM, BUT EMBOLIZATION WAS NOT CONDUCTED AS THERE WAS NO EVIDENCE OF OVERT BLEEDING. THE PATIENT'S GENERAL CONDITION GRADUALLY IMPROVED. AFTER THE THIRD HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE PATIENT'S LIVER FUNCTION IMPROVED TO CHILD-PUGH CLASS A (6), AND NO ASCITES WERE OBSERVED. HOWEVER, AFTER THE FOURTH CYCLE OF HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE CT SCAN REVEALED PROGRESSION OF THE VIABLE TUMOR AT THE ANTERIOR ASPECT OF THE HCC AND OTHER EXTENSIVE HCCS INVOLVING BOTH LOBES OF THE LIVER, ALONG WITH INCREASING AFP LEVELS. AFTER THE FAILURE OF HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, THE PATIENT WAS STARTED ON ATEZOLIZUMAB/BEVACIZUMAB. ATEZOLIZUMAB (TECENTRIQ 1200 MG PER DOSE; ROCHE INTERNATIONAL LLC., (B)(6), SWITZERLAND) AND BEVACIZUMAB (AVASTIN 15MG/KG PER DOSE; GENENTECH, (B)(6), CA, UNITED STATES) WERE ADMINISTERED EVERY 3 WK. FOLLOWING THE THIRD CYCLE OF IMMUNOTHERAPY, THE TREATMENT RESPONSE WAS FORMALLY EVALUATED USING A CT SCAN. WE OBSERVED A DECREASE IN ARTERIAL ENHANCEMENT IN EXTENSIVE HCCS INVOLVING BOTH HEMILIVERS, AND THE TUMOR RESPONSE WAS EVALUATED AS A PARTIAL RESPONSE ACCORDING TO THE MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS CRITERIA. SEVEN DAYS AFTER THE FIFTH CYCLE OF ATEZOLIZUMAB/BEVACIZUMAB, HE PRESENTED TO THE EMERGENCY ROOM DUE TO ABRUPT ABDOMINAL PAIN, RATED 8 ON THE NUMERICAL RATING SCALE. HISTORY OF PAST ILLNESS: APART FROM CHRONIC HEPATITIS C, THE PATIENT HAD NO SIGNIFICANT MEDICAL HISTORY. PERSONAL AND FAMILY HISTORY: THERE WAS NO FAMILY HISTORY OF ANY DISEASES OR CANCER. FINAL DIAGNOSIS: THE PATIENT WAS DIAGNOSED WITH AN INTRATUMORAL RUPTURE THAT OCCURRED DURING ATEZOLIZUMAB/BEVACIZUMAB TREATMENT FOR HCC. TREATMENT: EMERGENCY TRANSCATHETER HEMOSTASIS WAS PERFORMED DUE TO THE IDENTIFIED INTRATUMOR BLEEDING. ANGIOGRAPHY REVEALED ACTIVE CONTRAST EXTRAVASATION FROM THE S4 TUMOR. SELECTIVE EMBOLIZATION OF THESE VESSELS USING A GELATIN SPONGE AND LIPIODOL WAS PERFORMED. AFTER EMBOLIZATION, DYNAMIC CONTRAST-ENHANCED CT CONFIRMED THE COMPLETE HEMOSTASIS OF THE INTRATUMORAL HEMORRHAGE. OUTCOME AND FOLLOW-UP: DESPITE THE SUCCESSFUL EMBOLIZATION, THE PATIENT'S LIVER FUNCTION GRADUALLY DETERIORATED, AND HEPATORENAL SYNDROME DEVELOPED ON THE 10TH DAY AFTER EMBOLIZATION. THE PATIENT DIED 12 D AFTER EMBOLIZATION DUE TO THE WORSENING CONDITIONS OF LIVER AND KIDNEY FUNCTION. DISCUSSION: THE PRIMARY CHALLENGE AT PRESENT IS THE ABSENCE OF IDENTIFIED PREVENTION OR TREATMENT STRATEGIES FOR THIS UNCOMMON INTRATUMORAL HEMORRHAGE. FOLLOWING THE SECOND HEPATIC ARTERIAL INFUSION CHEMOTHERAPY, WE CONDUCTED ANGIOGRAPHY FOR PSEUDOANEURYSM; HOWEVER, EMBOLIZATION WAS NOT PERFORMED AS THERE WAS NO EVIDENCE OF BLEEDING. IN HINDSIGHT, EVEN IN THE ABSENCE OF APPARENT BLEEDING, PREVENTIVE EMBOLIZATION COULD HAVE BEEN CONSIDERED TO POTENTIALLY AVERT FATAL BLEEDING IN THE FUTURE. YET, THE EFFECTIVENESS OR SAFETY OF PROPHYLACTIC EMBOLIZATION FOR PSEUDOANEURYSM IN PATIENTS WITHOUT EVIDENCE OF INTRATUMORAL BLEEDING REMAINS UNDISCLOSED. IN SUMMARY, THIS CASE UNDERSCORES THE VARIED AND SOMETIMES FATAL BLEEDING COMPLICATIONS THAT CAN ARISE AFTER ATEZOLIZUMAB/BEVACIZUMAB TREATMENT IN PATIENTS WITH HEPATOCELLULAR CARCINOMA. PRODUCT QUALITY GROUP PROVIDED INVESTIGATIONAL RESULTS ON (B)(6) 2024 FOR ABSORBABLE GELATIN: THE COMPLAINT FOR 'ADVERSE EVENT MD/MDCP' FOR AN UNKNOWN BATCH OF GELFOAM ABSORBABLE MATERIAL WAS INVESTIGATED. THE INVESTIGATION INCLUDED REVIEWING APRRS FOR THE PRODUCT AND A MEDICAL DEVICE TREND REVIEW. THE FINAL SCOPE WAS DETERMINED TO BE ALL BATCHES OF GELFOAM MANUFACTURED BY PFIZER KALAMAZOO WITHIN THE 36 MONTHS (THE EXPIRY INTERVAL OF THE PRODUCT) PRIOR TO THE RECEIPT DATE OF THE COMPLAINT. A COMPLAINT SAMPLE WAS NOT RETURNED. NO RELATED QUALITY ISSUES WERE IDENTIFIED DURING THE INVESTIGATION. NO ROOT CAUSE OR CAPA WERE IDENTIFIED AS THE COMPLAINT WAS NOT CONFIRMED. NO RELATED QUALITY DEFECTS WERE IDENTIFIED THROUGH INVESTIGATION. THERE IS NO IMPACT ON MEDICAL DEVICE QUALITY, REGULATORY, VALIDATION, OR STABILITY. FOLLOW-UP (05SEP2024): THIS IS A FOLLOW-UP REPORT FROM PRODUCT QUALITY GROUP PROVIDING INVESTIGATION RESULTS., COMMENT: THE EVENTS HEPATIC FAILURE AND HEPATORENAL SYNDROME ARE ASSESSED AS SERIOUS, ASSOCIATED WITH THE PRODUCT ABSORBABLE GELATIN (GELFOAM), AND UNLISTED IN THE CDS OF THE PFIZER SUSPECT PRODUCT ABSORBABLE GELATIN. THIS CASE WILL BE REASSESSED WHEN ADDITIONAL INFORMATION IS RECEIVED.
Devices
| Seq | Brand | Generic | Product Code | Manufacturer | Model | Lot | UDI-DI |
|---|---|---|---|---|---|---|---|
| 935148 | GELFOAM | SPONGE, STERILE; CLASS III | LMF | PFIZER, INC. |
Patients
| Seq | Age | Sex | Outcome | Treatment |
|---|---|---|---|---|
| 1 | 63 YR | Male | Death | LIPIODOL [DOSAGE FORM:]| LIPIODOL [DOSAGE FORM:]| LIPIODOL [DOSAGE FORM:] |