b'IMJUDO (tremelimumab-actl) injection, for intravenous use 3Serious adverse reactions occurred in 41% of patients who receivedTable 5. Laboratory Abnormalities Worsening from BaselinePregnancy TestingIMJUDOincombinationwithdurvalumab.SeriousadverseOccurring in20% of Patients in the HIMALAYA study (contd) Verifypregnancystatusoffemalesofreproductivepotential reactions in 1% of patients included hemorrhage (6%), diarrheaIMJUDO andSorafenib prior to initiating treatment with IMJUDO. (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomitingDurvalumab Contraception(1.3%), acute kidney injury (1.3%), and anemia (1.3%). FatalLaboratoryAny grade 1Grade 3 1Any grade 1Grade 3 1 Advisefemalesofreproductivepotentialtouseeffective adverse reactions occurred in 8% of patients who received IMJUDOAbnormality (%) 2 or 4 (%) 2 or 4 contraception during treatment with IMJUDO and for 3 months in combination with durvalumab, including death (1%), hemorrhage(%) 2 (%) 2 afterthelastdose.RefertothePrescribingInformationfor intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%),theagentsadministeredincombinationwithIMJUDOfor hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). TheChemistry recommended contraception duration, as appropriate.most common adverse reactions (occurring in20% of patients)Glucose increased 39 14 29 4 Pediatric Usewere rash, diarrhea, fatigue, pruritus, musculoskeletal pain, andCalcium decreased 34 0 43 0.3abdominal pain. The safety and effectiveness of tremelimumab-actl have not been Permanent discontinuation of the treatment regimen due to anAlbumin decreased 31 0.5 37 1.7 established in pediatric patients.adverse reaction occurred in 14% of patients; the most commonPotassium 28 3.8 21 2.6 Geriatric Useadverse reactions leading to treatment discontinuation ( 1%) wereincreased Ofthe393patientswithuHCCtreatedwithIMJUDOin hemorrhage (1.8%), diarrhea (1.5%), AST increased (1%), andCreatinine increased 21 1.3 15 0.9 combination with durvalumab, 50% of patients were 65 years hepatitis (1%). Hematology or older and 13% of patients were 75 years or older. No overall Dosage interruptions or delay of the treatment regimen due to anHemoglobin 52 4.8 40 6 differences in safety or efficacy of IMJUDO have been observed adverse reaction occurred in 35% of patients. Adverse reactionsdecreased between patients 65 years or older and younger adult patients.which required dosage interruption or delay in1% of patientsLymphocytes 41 11 39 10 PATIENT COUNSELING INFORMATIONincludedALTincreased(3.6%),diarrhea(3.6%),rash(3.6%),decreased Advise the patient to read the FDA-approved patient labelingSource: An Open-Access, Interactive Decision-Support Tool to Facilitate Guideline-Driven Care for Hepatocellular Carcinoma. Gastroenterology Res. 2022 amylase increased (3.4%), AST increased (3.1%), lipase increasedPlatelets decreased 29 1.6 35 3.1 (Medication Guide) in the full Prescribing Information.Dec;15(6):297-307. doi: 10.14740/gr1573. Epub 2022 Dec 1. PMID: 36660470; PMCID: PMC9822660.(2.8%),pneumonia(1.5%),hepatitis(1.5%),pyrexia(1.5%),Immune-Mediated Adverse Reactionsanemia (1.3%), thrombocytopenia(1%), hyperthyroidism (1%),Leukocytes 20 0.8 30 1.1 Inform patients of the risk of immune-mediated adverse reactions pneumonitis (1%), and blood creatinine increased (1%). decreasedTable 4 summarizes the adverse reactions that occurred in patients1Graded according to NCI CTCAE version 4.03. thatmayrequirecorticosteroidtreatmentandinterruptionoru From Page 592 discontinuationofIMJUDOincombinationwithdurvalumab, treatedwithIMJUDOincombinationwithdurvalumabinthe Each test incidence is based on the number of patients who had bothincluding[seeWarningsandPrecautions(5.1)inthefull HIMALAYA study. baseline and at least one on-study laboratory measurement available:Prescribing Information]: is whether an abbreviated magnetic resonance imag- ledtoahighproportionofhepatocellularcarci-Table 4. Adverse Reactions Occurring in10% Patients in theIMJUDO with durvalumab (range: 367-378) and sorafenib (range: 344-352). Pneumonitis:Advisepatientstocontacttheirhealthcareing (aMRI) is more effective at detecting hepatocel- noma being detected at advanced stages, according HIMALAYA study USE IN SPECIFIC POPULATIONS provider immediately for any new or worsening cough, chest pain, or shortness of breath. lular carcinoma in early stages than ultrasound, theto the article.IMJUDO andSorafenib PregnancyDurvalumab (N=374) Risk summary Colitis: Advise patients to contact their healthcare providercurrent standard of care.Thereviewarticleprovidesasummaryofthe (N=388) Based on findings from animal studies and its mechanism ofimmediately for diarrhea, blood or mucus in stools, or severe abdominal pain. The study is scheduled to recruit 4,700 veteransexisting gaps in hepatocellular carcinoma care by Adverse Reaction All Grades Grade 3-4 All Grades Grade 3-4action, IMJUDO can cause fetal harm when administered to aHepatitis: Advise patients to contact their healthcare provider (%) (%) (%) (%) pregnant woman [see Clinical Pharmacology (12.1) in the fullwith cirrhosis from 47 VAMCs. Cirrhosis is a knownreviewingdataonsurveillancerates,disparities Gastrointestinal disorders Prescribing Information]. There are no available data on the use ofimmediately for jaundice, severe nausea or vomiting, pain on 1 IMJUDO in pregnant women. In animal studies, CTLA-4 blockadethe right side of abdomen, lethargy, or easy bruising or bleeding. risk factor for liver cancer.associated with hepatocellular carcinoma surveil-Diarrhea 1 27 6 45 4.3 is associated with increased risk of immune-mediated rejection ofEndocrinopathies: Advise patients to contact their healthcareByincreasingearlydetection,ourmedicallance and targeted efforts to improve hepatocellular Abdominal pain 20 1.8 24 4 the developing fetus and fetal death (see Data). provider immediately for signs or symptoms of hypothyroidism, Nausea 12 0 14 0 Human immunoglobulin G2 (IgG2) is known to cross the placentalhyperthyroidism,adrenalinsufficiency,type1diabetesresearchers believe VA will be able to increase suc- carcinomasurveillance.Italsointroducesafree, Skin and subcutaneous tissue disorders barrier; therefore, IMJUDO has the potential to be transmitted frommellitus, or hypophysitis. cessful outcomes, the VA spokesperson added. open-accessdecision-supporttoolthathasbeen Rash 1 32 2.8 57 12 the mother to the developing fetus. Advise pregnant women andNephritis: Advise patients to contact their healthcare provider females of reproductive potential of the potential risk to a fetus. immediately for signs or symptoms of nephritis. Accordingtoareviewarticlepublishedindeveloped to assist healthcare professionals in the Pruritus 23 0 6 0.3 Dermatological Reactions: Advise patients to contact their Metabolism and nutrition disorders In the U.S. general population, the estimated background riskhealthcare provider immediately for signs or symptoms ofGastroenterologyResearch,hepatocellularcarci- surveillance,diagnosis,stagingandtreatmentof of major birth defects and miscarriage in clinically recognized Decreased appetite 17 1.3 18 0.8 pregnancies is 2% to 4% and 15% to 20%, respectively. severe dermatological reactions. noma is the fastest-rising cause of cancer mortalitypatients with hepatocellular carcinoma. General disorders and administration site conditions Pancreatitis:Advisepatientstocontacttheirhealthcare 1 Data provider immediately for signs or symptoms of pancreatitis. in the United States. It is the fourth-most-commonThe tool incorporates guideline-based recommen-Fatigue 1 26 3.9 30 6 Animal Data Other Immune-Mediated Adverse Reactions: Advise patientscauseofcancer-relatedmortalityworldwide,anddationsonhepatocellularcarcinomasurveillance Pyrexia 13 0.3 9 0.3 Inareproductionstudy,administrationoftremelimumab-actlto contact their healthcare provider immediately for signs or Psychiatric disorders to pregnant cynomolgus monkeys during the period of organo-symptoms of aseptic meningitis, immune thrombocytopenia,incidenceincreasedby75%worldwidebetweenand staging systems and could improve appropri-genesis was not associated with maternal toxicity or effects onmyocarditis, hemolytic anemia, myositis, uveitis, keratitis, and Insomnia 10 0.3 4.3 0 embryo-fetaldevelopmentatexposurelevelsapproximatelymyasthenia gravis. 1990 and 2015, with 800,000 annual deaths. Dataate and timely triage of patients to appropriate care. Endocrine disorders1 4 to 31-times higher than those observed at a recommended doseInfusion-Related Reactions: from the Global Burden of Disease Study reportedThistoolwasdevelopedbytheHepatocellular Hypothyroidism 14 0 6 0 range of 75 mg to 300 mg based on area under the curve (AUC). Musculoskeletal and Connective Tissue Disorders CTLA-4 plays a role in maintaining maternal immune toleranceAdvise patients to contact their healthcare provider immediatelythatlivercancerdeathsincreasedby25%fromCarcinomaSteeringCommitteeoftheChronic to the fetus to preserve pregnancy and in immune regulation offorsignsorsymptomsofinfusion-relatedreactions[see2Musculoskeletal22 2.6 17 0.8 WarningsandPrecautions(5.2)inthefullPrescribing2010 to 2019. LiverDiseaseFoundationandistargetedtoward pain 1 the newborn. In a murine model of pregnancy, CTLA-4 blockadeInformation].1 resulted in increased resorptions and reduced live fetuses. MatedThereviewarticlesupportstheimportanceofcliniciansacrossspecialtieswhomayencounterRepresents a composite of multiple related terms. genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-)Embryo-Fetal Toxicity:gave birth to CTLA-4+/- offspring and offspring deficient in CTLA-4AdvisefemalesofreproductivepotentialthatIMJUDOearlydetectionofhepatocellularcarcinoma.Theliver lesions during routine care or as part of dedi-Table 5 summarizes the laboratory abnormalities that occurred in patients treated with IMJUDO in combination with durvalumab(homozygous negative, CTLA-4-/-) that appeared healthy at birth.can cause harm to a fetus and to inform their healthcarearticle found that early detection of hepatocellularcated hepatocellular carcinoma surveillance.The CTLA-4-/- homozygous negative offspring developed signs ofprovider of a known or suspected pregnancy [see Warnings in the HIMALAYA study. a lymphoproliferative disorder and died by 3 to 4 weeks of ageand Precautions (5.3) and Use in Specific Populations (8.1,carcinomaimprovesoptionsforpotentiallycura- 1Ju MR, Karalis JD, Chansard M, Augustine MM, Mortensen E, Wang Table 5. Laboratory Abnormalities Worsening from Baselinewith multiorgan tissue destruction. Based on its mechanism of8.3) in the full Prescribing Information]. tive treatment, which is associated with significantlySC, Porembka MR, Zeh HJ 3rd, Yopp AC, Polanco PM. Variation of Occurring in20% of Patients in the HIMALAYA study action, fetal exposure to tremelimumab-actl may increase the riskAdvisefemalesofreproductivepotentialtouseeffective of developing immune-mediated disorders or altering the normalcontraception during treatment and for 3 months after the lastimproved five-year survival. Hepatocellular Carcinoma Treatment Patterns and Survival Across IMJUDO andSorafenib immune response. dose of IMJUDO [see Use in Specific Populations (8.3) in theGeographic Regions in a Veteran Population. Ann Surg Oncol. 2022 Durvalumab Patients diagnosed with advanced stages of hepa-LaboratoryAny grade 1Grade 3 1Any grade 1Grade 3 1 Lactation full Prescribing Information]. Dec;29(13):8413-8420. doi: 10.1245/s10434-022-12390-7. Epub 2022 2 2 Risk Summary Lactation: tocellularcarcinomasurviveamedianofoneAug 26. PMID: 36018517.Abnormality (%) or 4 (%) or 4(%) 2 (%) 2 There are no data on the presence of tremelimumab-actl in humanAdvise female patients not to breastfeed while taking IMJUDOyearanduptotwoyearswithsystemictherapy.2 Chemistry milk, its effects on a breastfed child, or on milk production.and for 3 months after the last dose [see Warnings andWong RJ, Jayasekera C, Jones P, Kanwal F, Singal AG, Ahmed A, Ta-Maternal IgG is known to be present in human milk. The effectsPrecautions (5.3) and Use in Specific Populations (8.2) in theEffectiveimplementationofhepatocellularcarci- glienti R, Younossi Z, Kulik L, Mehta N. An Open-Access, Interactive Aspartate 63 27 55 21 of local gastrointestinal exposure and limited systemic exposurefull Prescribing Information].Aminotransferasenoma screening and surveillance in patients withDecision-Support Tool to Facilitate Guideline-Driven Care for Hepa-increased in the breastfed child to IMJUDO are unknown. Because of thetocellular Carcinoma. Gastroenterology Res. 2022 Dec;15(6):297-307. potential for serious adverse reactions in the breastfed child,Manufactured for: AstraZeneca Pharmaceuticals LPcirrhosisisassociatedwithimprovedearly-stage Alanine 56 18 53 12 advise women not to breastfeed during treatment with IMJUDOWilmington, DE 19850 doi: 10.14740/gr1573. Epub 2022 Dec 1. PMID: 36660470; PMCID: Aminotransferaseand for 3 months after the last dose. Refer to the Prescribingdiagnosis of hepatocellular carcinoma, while sub- PMC9822660.increased Information for agents administered in combination with IMJUDOManufactured By: AstraZeneca AB, Sdertlje, Sweden SE-15185 optimal hepatocellular carcinoma surveillance has Sodium decreased 46 15 40 11 for breastfeeding recommendations, as appropriate. US License No. 2059Bilirubin increased 41 8 47 11 Females and Males of Reproductive Potential IMJUDO is a registered trademark of the AstraZeneca groupAlkaline 41 8 44 5 IMJUDO can cause fetal harm when administered to a pregnantof companies.Phosphatase woman[seeUseinSpecificPopulations(8.1)inthefullAstraZeneca 2023increased Prescribing Information]. 11/22 US-73456 3/23 71US-72576_US-73769_US-73456 Imfinzi-Imjudo US Medicine - The Compendium.indd 9 4/28/23 4:18 PM'