b'EPKINLYTM (epcoritamab-bysp) injection, for subcutaneous use. Rx Only.the most recent administration of EPKINLY, the median time to onset of ICANSPermanent discontinuation of EPKINLY due to an adverse reaction occurred inIn the U.S. general population, the estimated background risk of major birth Brief Summary of Full Prescribing Information. See Full PI.was 3 days (range: 1 to 13 days). The median duration of ICANS was 4 days3.8% of patients. Adverse reactions which resulted in permanent discontinuationdefects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% WARNING: CYTOKINE RELEASE SYNDROME and IMMUNE(range: 0 to 8 days) with ICANS resolving in 90% of patients with supportive care.of EPKINLY included COVID-19, CRS, ICANS, pleural effusion, and fatigue.to 20%, respectively. EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROMEClinical manifestations of ICANS included, but were not limited to, confusionalDosage interruptions of EPKINLY due to an adverse reaction occurred in 34% ofLactationRisk Summary Cytokine release syndrome (CRS), including serious or life-threateningstate, lethargy, tremor, dysgraphia, aphasia, and non-convulsive status epilepticus.patients who received EPKINLY. Adverse reactions which required dosageThere is no information regarding the presence of epcoritamab-bysp in human reactions, can occur in patients receiving EPKINLY. Initiate treatmentThe onset of ICANS can be concurrent with CRS, following resolution of CRS, orinterruption in3% of patients included CRS, neutropenia, sepsis, andmilk, the effect on the breastfed child, or milk production. Because maternal IgG is with the EPKINLY step-up dosing schedule to reduce the incidence andin the absence of CRS.thrombocytopenia.present in human milk, and there is potential for epcoritamab-bysp absorption severity of CRS. Withhold EPKINLY until CRS resolves or permanentlyMonitor patients for potential ICANS following EPKINLY. At the first signs orThe most common ( 20%) adverse reactions were CRS, fatigue, musculoskeletalleading to serious adverse reactions in a breastfed child, advise women not to discontinue based on severity.symptoms of ICANS, immediately evaluate patient and provide supportive therapypain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. Thebreastfeed during treatment with EPKINLY and for 4 months after the last dose. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS),based on severity. Withhold or discontinue EPKINLY per recommendations andmost common Grade 3 to 4 laboratory abnormalities ( 10%) were decreasedFemales and Males of Reproductive Potential: EPKINLY may cause fetal harm including life-threatening and fatal reactions, can occur with EPKINLY.consider further management per current practice guidelines. lymphocyte count, decreased neutrophil count, decreased white blood cell count,when administered to a pregnant woman. Monitor patients for neurological signs or symptoms of ICANS duringPatients who experience signs or symptoms of ICANS or any other adversedecreased hemoglobin, and decreased platelets.Pregnancy Testing: Verify pregnancy status in females of reproductive potential treatment. Withhold EPKINLY until ICANS resolves or permanentlyreactions that impair cognition or consciousness should be evaluated, includingAdverse Reactions10% in patients treated with EPKINLY were as follows (allprior to initiating EPKINLY. discontinue based on severity.potential neurology evaluation, and patients at increased risk should be advised notgrades, grade 3 or 4#): cytokine release syndrome* (51%, 2.5%), fatiguea (29%, to drive and to refrain from operating heavy or potentially dangerous machinery2.5%), injection site reactionsb (27%, 0%), pyrexia (24%, 0%), edemac (14%,ContraceptionFemales: Advise females of reproductive potential to use effective INDICATIONS AND USAGE: EPKINLY is indicated for the treatment of adultuntil resolution.1.9%), dmusculoskeletal pain (28%, 1.3%), abdominal paine (23%, 1.9%), diarrheacontraception during treatment with EPKINLY and for 4 months after the last patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), notInfections: EPKINLY can cause serious and fatal infections. In the clinical trial,(20%, 0%), nausea (20%, 1.3%), vomiting (12%, 0.6%), rashf (15%, 0.6%),dose. otherwise specified, including DLBCL arising from indolent lymphoma, and high- serious infections, including opportunistic infections were reported in 15% ofheadache (13%, 0.6%), decreased appetite (12%, 0.6%), cardiac arrhythmiasgPediatric Use: The safety and efficacy of EPKINLY in pediatric patients have not grade B-cell lymphoma after two or more lines of systemic therapy. Thispatients treated with EPKINLY at the recommended dose with Grade 3 or 4(10%, 0.6%). Adverse reactions were graded based on CTCAE Version 5.0;been established. indication is approved under accelerated approval based on response rate andinfections in 14% and fatal infections in 1.3%. The most common Grade 3 or#Only grade 3 adverse reactions occurred; *CRS was graded using ASTCTGeriatric Use: In patients with relapsed or refractory LBCL who received durability of response. Continued approval for this indication may be contingentgreater infections were sepsis, COVID-19, urinary tract infection, pneumonia, andconsensus criteria (Lee et al., 2019); a Fatigue includes asthenia, fatigue, lethargy;EPKINLY in the clinical trial, 49% were 65 years of age or older, and 19% were upon verification and description of clinical benefit in a confirmatory trial(s).upper respiratory tract infection.bInjection site reactions includes injection site erythema, injection site75 years of age or older. No clinically meaningful differences in safety or efficacy IMPORTANT DOSING INFORMATION: Administer EPKINLY to well- Monitor patients for signs and symptoms of infection prior to and during treatmenthypertrophy, injection site inflammation, injection site mass, injection site pain,were observed between patients 65 years of age or older compared with younger hydrated patients. Premedicate before each dose in Cycle 1. EPKINLY shouldwith EPKINLY and treat appropriately. Avoid administration of EPKINLY ininjection site pruritus, injection site rash, injection site reaction, injection siteadult patients. only be administered by a qualified healthcare professional with appropriatepatients with active infections. Provide PJP prophylaxis prior to initiatingswelling, injection site urticaria; cEdema includes edema, edema peripheral, faceManufactured by: Genmab US, Inc. Plainsboro, NJ 08536, USA 1-855-4GENMAB (1-855-443-6622) medical support to manage severe reactions such as cytokine release syndrometreatment with EPKINLY; consider initiating prophylaxis against herpes virusedema, generalized edema, peripheral swelling; dMusculoskeletal pain includesU.S. License Number: 2293(CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).prior to starting EPKINLY.back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain,Marketed by: Genmab US, Inc. Plainsboro, NJ 08536 and AbbVie Inc. North Chicago, IL 60064 myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, spinal pain; Administer EPKINLY subcutaneously according to the dosage schedule in Table 1Withhold or consider permanent discontinuation of EPKINLY based on severity.eAbdominal pain includes abdominal discomfort, abdominal pain, abdominal painEPKINLY is a trademark owned by Genmab A/S to reduce the incidence and severity of CRS. Due to the risk of CRS and ICANS,Cytopenias: EPKINLY can cause serious or severe cytopenias, includinglower, abdominal pain upper, abdominal tenderness; fRash includes dermatitis patients should be hospitalized for 24 hours after administration of the Cycle 1neutropenia, anemia, and thrombocytopenia. Among patients who received thebullous, erythema, palmar erythema, penile erythema, rash, rash erythematous,2023 Genmab A/S. All rights reserved. Day 15 dosage of 48 mg.recommended dosage in the clinical trial, Grade 3 or 4 decreased neutrophilsrash maculo-papular, rash pustular, recall phenomenon, seborrheic dermatitis, skinREF-01422 May 2023RECOMMENDED DOSAGE: EPKINLY is for subcutaneous injection only.occurred in 32%, decreased hemoglobin in 12%, and decreased platelets in 12% ofexfoliation; gCardiac arrhythmias includes bradycardia, sinus bradycardia, sinus Administer EPKINLY in 28-day cycles until disease progression or unacceptablepatients. Febrile neutropenia occurred in 2.5%.tachycardia, supraventricular extrasystoles, supraventricular tachycardia, toxicity. EPKINLY Dosage Schedulecycle 1, day 1: EPKINLY 0.16 mg (step- Monitor complete blood counts throughout treatment. Based on the severity oftachycardia. up dose 1); day 8: EPKINLY 0.8 mg (step-up dose 2); day 15: EPKINLY 48 mgcytopenias, temporarily withhold or permanently discontinue EPKINLY. ConsiderClinically relevant adverse reactions in 10% of patients who received EPKINLY (first full dose); day 22: EPKINLY 48 mg; cycles 2 and 3, days 1, 8, 15, and 22:prophylactic granulocyte colony-stimulating factor administration as applicable.included ICANS, sepsis, pleural effusion, COVID-19, pneumonia (including EPKINLY 48 mg; cycles 4 to 9, days 1 and 15: EPKINLY 48 mg; cycles 10 andEmbryo-Fetal Toxicity: Based on its mechanism of action, EPKINLY may causepneumonia and COVID-19 pneumonia), tumor flare, febrile neutropenia, upper beyond, day 1: EPKINLY 48 mg.fetal harm when administered to a pregnant woman. Advise pregnant women ofrespiratory tract infections, and tumor lysis syndrome. CONTRAINDICATIONS: None.the potential risk to the fetus. Advise females of reproductive potential to useSelect laboratory abnormalities*20% that worsened from baseline in patients WARNINGS AND PRECAUTIONSeffective contraception during treatment with EPKINLY and for 4 months after thetreated with EPKINLY1 were as follows (all grades, grade 3 or 4): lymphocyte Cytokine Release Syndrome: EPKINLY can cause CRS, including serious orlast dose.count decreased (87%, 77%), hemoglobin decreased (62%, 12%), white blood life-threatening reactions. Cytokine release syndrome occurred in 51% of patientsADVERSE REACTIONS, Clinical Trials Experiencecells decreased (53%, 22%), neutrophils decreased (50%, 32%), platelets receiving EPKINLY at the recommended dose in the clinical trial, with Grade 1Because clinical trials are conducted under widely varying conditions, adversedecreased (48%, 12%), sodium decreased (56%, 2.6%), phosphate decreased2 CRS occurring in 37%, Grade 2 in 17%, and Grade 3 in 2.5% of patients.reaction rates observed in the clinical trials of a drug cannot be directly compared(56%, N/A), aspartate aminotransferase increased (48%, 4.6%), alanine Recurrent CRS occurred in 16% of patients. Of all the CRS events, most (92%)to rates in the clinical trials of another drug and may not reflect the rates observedaminotransferase increased (45%, 5.3%), potassium decreased (34%, 5.3%), occurred during Cycle 1. In Cycle 1, 9% of CRS events occurred after the 0.16 mgin practice.magnesium decreased (31%, 0%), creatinine increased (24%, 3.3%), potassium dose on Cycle 1 Day 1, 16% after the 0.8 mg dose on Cycle 1 Day 8, 61% after theThe safety of EPKINLY was evaluated in EPCORE NHL-1, a single-arm study ofincreased (21%, 1.3%).*Laboratory abnormalities were graded based on CTCAE 48 mg dose on Cycle 1 Day 15, and 6% after the 48 mg dose on Cycle 1 Day 22.patients with relapsed or refractory LBCL after two or more lines of systemicVersion 5.0; 1The denominator used to calculate the rate varied from 146 to 153 The median time to onset of CRS from the most recent administered EPKINLYbased on the number of patients with a baseline value and at least one post-dose across all doses was 24 hours (range: 0 to 10 days). The median time to onsettherapy, including DLBCL not otherwise specified, DLBCL arising from indolenttreatment value. 2CTCAE Version 5.0 does not include numeric thresholds for after the first full 48 mg dose was 21 hours (range: 0 to 7 days). CRS resolved inlymphoma, high grade B-cell lymphoma, and other B-cell lymphomas. A total ofgrading of hypophosphatemia; all grades represent patients with lab value Lower 98% of patients and the median duration of CRS events was 2 days (range: 1 to157 patients received EPKINLY via subcutaneous injection until diseaseLimit of Normal (LLN). 27 days). progression or unacceptable toxicities according to the following 28-day cycle schedule: Cycle 1: EPKINLY 0.16 mg on Day 1, 0.8 mg on Day 8, 48 mg onDRUG INTERACTIONS: For certain CYP substrates, minimal changes in the In patients who experienced CRS, the signs and symptoms included pyrexia,Days 15 and 22; Cycles 2-3: EPKINLY 48 mg on Days 1, 8, 15, and 22;concentration may lead to serious adverse reactions. Monitor for toxicity or drug hypotension, hypoxia, dyspnea, chills, and tachycardia. Concurrent neurologicalCycles 4-9: EPKINLY 48 mg on Days 1 and 15; Cycles 10 and beyond:concentrations of such CYP substrates when co-administered with EPKINLY. adverse reactions associated with CRS occurred in 2.5% of patients and includedEPKINLY 48 mg on Day 1Epcoritamab-bysp causes release of cytokines that may suppress activity of CYP headache, confusional state, tremors, dizziness, and ataxia.Of the 157 patients treated, the median age was 64 years (range: 20 to 83), 60%enzymes, resulting in increased exposure of CYP substrates. Increased exposure of Initiate therapy according to EPKINLY step-up dosing schedule. Administermale, and 97% had an ECOG performance status of 0 or 1. Race was reported inCYP substrates is more likely to occur after the first dose of EPKINLY on Cycle 1 pretreatment medications to reduce the risk of CRS and monitor patients for133 (85%) patients; of these patients, 61% were White, 19% were Asian, and 0.6%Day 1 and up to 14 days after the first 48 mg dose on Cycle 1 Day 15, and during potential CRS following EPKINLY accordingly. Following administration of thewere Native Hawaiian or Other Pacific Islander. There were no Black or Africanand after CRS. first 48 mg dose, patients should be hospitalized for 24 hours. At the first signs orAmerican or Hispanic or Latino patients treated in the clinical trial as reported.USE IN SPECIFIC POPULATIONS symptoms of CRS, immediately evaluate patients for hospitalization, manage perThe median number of prior therapies was 3 (range: 2 to 11). The study excludedPregnancyRisk Summary: Based on the mechanism of action, EPKINLY may current practice guidelines, and administer supportive care as appropriate.patients with CNS involvement of lymphoma, allogeneic HSCT or solid organcause fetal harm when administered to a pregnant woman. There are no available Withhold or discontinue EPKINLY based on the severity of CRS.transplant, an ongoing active infection, and any patients with known impaired T- data on the use of EPKINLY in pregnant women to evaluate for a drug-associated Patients who experience CRS (or other adverse reactions that impaircell immunity. The median duration of exposure for patients receiving EPKINLYrisk. No animal reproductive or developmental toxicity studies have been consciousness) should be evaluated and advised not to drive and to refrain fromwas 5 cycles (range: 1 to 20 cycles).conducted with epcoritamab-bysp. operating heavy or potentially dangerous machinery until resolution.Serious adverse reactions occurred in 54% of patients who received EPKINLY.Epcoritamab-bysp causes T-cell activation and cytokine release; immune Immune Effector Cell-Associated Neurotoxicity Syndrome: EPKINLY canSerious adverse reactions in2% of patients included CRS, infections (includingactivation may compromise pregnancy maintenance. In addition, based on cause life-threatening and fatal immune effector cell-associated neurotoxicitysepsis, COVID-19, pneumonia, and upper respiratory tract infections), pleuralexpression of CD20 on B-cells and the finding of B-cell depletion in non-pregnant syndrome (ICANS). Immune Effector Cell-Associated Neurotoxicity Syndromeeffusion, febrile neutropenia, fever, and ICANS. Fatal adverse reactions occurredanimals, epcoritamab-bysp can cause B-cell lymphocytopenia in infants exposed occurred in 6% (10/157) of patients receiving EPKINLY at the recommended dosein 3.8% of patients who received EPKINLY, including COVID-19 (1.3%),to epcoritamab-bysp in-utero. Human immunoglobulin G (IgG) is known to cross in the clinical trial, with Grade 1 ICANS in 4.5% and Grade 2 ICANS in 1.3% ofhepatotoxicity (0.6%), ICANS (0.6%), myocardial infarction (0.6%), andthe placenta; therefore, EPKINLY has the potential to be transmitted from the patients. There was one (0.6%) fatal ICANS occurrence. Of the 10 ICANS events,pulmonary embolism (0.6%).mother to the developing fetus. Advise women of the potential risk to the fetus.9 occurred within Cycle 1 of EPKINLY treatment, with a median time to onset of ICANS of 16.5 days (range: 8 to 141 days) from the start of treatment. Relative to'