b'DO NOT RE-SIZELAB-11532/COM-US-EPK-0001102 MASTEREPKINLY (epcoritamab-bysp) injection, for subcutaneous use. Rx Only. PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATIONcurrent practice guidelines, and administer supportive care as appropriate.arising from indolent lymphoma, high grade B-cell lymphoma, and other WARNING: CYTOKINE RELEASE SYNDROME AND IMMUNE EFFECTORWithhold or discontinue EPKINLY based on the severity of CRS. B-cell lymphomas. A total of 157 patients with LBCL received EPKINLY via CELL-ASSOCIATED NEUROTOXICITY SYNDROME Patients who experience CRS (or other adverse reactions that impair subcutaneous injection until disease progression or unacceptable toxicities Cytokine release syndrome (CRS), including serious or life-consciousness) should be evaluated and advised not to drive and to refrainaccording to the following 28-day cycle schedule:Cycle1: EPKINLY 0.16mg threatening reactions, can occur in patients receiving EPKINLY.from operating heavy or potentially dangerous machinery until resolution. on Day1, 0.8mg on Day8, 48mg on Days15 and 22; Cycles2-3: EPKINLY Initiate treatment with the EPKINLY step-up dosage schedule to48mg on Days1, 8, 15, and 22; Cycles4-9: EPKINLY 48mg on Days1 and reduce the incidence and severity of CRS. Withhold EPKINLY untilImmune Effector Cell-Associated Neurotoxicity Syndrome 15; Cycles10 and beyond: EPKINLY 48mg on Day1.CRS resolves or permanently discontinue based on severity. EPKINLY can cause life-threatening and fatal immune effector Of the 157 patients treated, the median age was 64 years (range: 20 to 83), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS),cell-associated neurotoxicity syndrome (ICANS). 60% were male, and 97% had an ECOG performance status of 0 or 1. Race including life-threatening and fatal reactions, can occur withRelapsed or Refractory Large B-cell Lymphoma (LBCL) was reported in 133 (85%) patients; of these patients, 61% were White, EPKINLY. Monitor patients for neurological signs or symptoms ofICANS occurred in 6% (10/157) of patients with LBCL receiving EPKINLY19% were Asian, and 0.6% were Native Hawaiian or Other Pacific Islander. ICANS during treatment. Withhold EPKINLY until ICANS resolves orat the recommended 2-step up dosage schedule in EPCORE NHL-1, withThere were no Black or African American or Hispanic or Latino patients permanently discontinue based on severity. Grade 1 ICANS in 4.5% and Grade2 ICANS in 1.3% of patients. There wastreated in the clinical trial as reported. The median number of prior therapies one (0.6%) fatal ICANS occurrence. Of the 10ICANS events, 9 occurredwas 3 (range: 2 to 11). The study excluded patients with CNS involvement INDICATIONS AND USAGE within Cycle1 of EPKINLY treatment, with a median time to onset of ICANSof lymphoma, allogeneic HSCT or solid organ transplant, an ongoing active DLBCL and High-grade B-cell Lymphoma:EPKINLY is indicated for theof 16.5days (range: 8 to 141days) from the start of treatment. Relativeinfection, and any patients with known impaired T-cell immunity.The to the most recent administration of EPKINLY, the median time to onset ofmedian duration of exposure for patients receiving EPKINLY was 5 cycles treatment of adult patients with relapsed or refractory diffuse large B-cellICANS was 3days (range: 1 to 13days). The median duration of ICANS was(range: 1 to 20 cycles).lymphoma (DLBCL), not otherwise specified, including DLBCL arising from4days (range: 0 to 8days) with ICANS resolving in 90% of patients with indolent lymphoma, and high-grade B-cell lymphoma after two or more linessupportive care. Serious adverse reactions occurred in 54% of patients who received of systemic therapy. This indication is approved under accelerated approvalEPKINLY. Serious adverse reactions in2% of patients included CRS, based on response rate and durability of response. Continued approval forRelapsed or Refractory Follicular Lymphoma (FL) infections (including sepsis, COVID-19, pneumonia, and upper respiratory this indication may be contingent upon verification and description of clinicalICANS occurred in 6% (8/127) of patients with FL receiving EPKINLY tract infections), pleural effusion, febrile neutropenia, fever, and ICANS. benefit in a confirmatory trial(s). following the 2-step up dosage schedule in EPCORE NHL-1, with Grade 1Fatal adverse reactions occurred in 3.8% of patients who received EPKINLY, Follicular Lymphoma:EPKINLY is indicated for the treatment of adult ICANS in 3.9% and Grade 2 ICANS in 2.4% of patients. The median timeincluding COVID-19 (1.3%), hepatotoxicity (0.6%), ICANS (0.6%), myocardial patients with relapsed or refractory follicular lymphoma (FL) after two orto onset of ICANS was 21.5 days (range: 14-66 days) from the start ofinfarction (0.6%), and pulmonary embolism (0.6%).more lines of systemic therapy.This indication is approved under treatment. Relative to the most recent administration of EPKINLY, the medianPermanent discontinuation of EPKINLY due to an adverse reaction occurred accelerated approval based on response rate and durability of response.time to onset of ICANS was 3 days (range: 0.4 to 7 days). The medianin 3.8% of patients. Adverse reactions which resulted in permanent Continued approval for this indication may be contingent upon verificationduration of ICANS was 2 days (range: 1-7 days) with ICANS resolving indiscontinuation of EPKINLY included COVID-19, CRS, ICANS, pleural effusion, and description of clinical benefit in a confirmatory trial(s). 100% of patients.and fatigue. Dosage interruptions of EPKINLY due to an adverse reaction IMPORTANT DOSING INFORMATION: Administer EPKINLY to well-hydratedFor patients with LBCL or FL, clinical manifestations of ICANS included, butoccurred in 34% of patients who received EPKINLY. Adverse reactions which patients.EPKINLY should only be administered by a qualified healthcarewere not limited to, confusional state, lethargy, tremor, dysgraphia, aphasia,required dosage interruption in3% of patients included CRS, neutropenia, professional with appropriate medical support to manage severe reactionsand non-convulsive status epilepticus. The onset of ICANS can be concurrentsepsis, and thrombocytopenia.such as cytokine release syndrome (CRS) and immune effector with CRS, following resolution of CRS, or in the absence of CRS. MonitorThe most common ( 20%) adverse reactions were CRS, fatigue,cell-associated neurotoxicity syndrome (ICANS).Administer EPKINLYpatients for potential ICANS following EPKINLY. At the first signs or symptomsmusculoskeletal pain, injection site reactions, pyrexia, abdominal pain, subcutaneously according to the step-up dosage schedule in Table 1 forof ICANS, immediately evaluate patient and provide supportive therapynausea, and diarrhea. The most common Grade3 to 4 laboratorypatients with DLBCL or high-grade B-cell Lymphoma, or Table 2 for patientsbased on severity. Withhold or discontinue EPKINLY per recommendationsabnormalities ( 10%) were decreased lymphocyte count, decreased with FL to reduce the incidence and severity of CRS. Due to the risk of CRSand consider further management per current practice guidelines.neutrophil count, decreased white blood cell count, decreased hemoglobin, and ICANS, monitor all patients for signs and symptoms.For Patients withPatients who experience signs or symptoms of ICANS or any other adverseand decreased platelets.DLBCL or High-grade B-cell Lymphoma: Patients should be hospitalized forreactions that impair cognition or consciousness should be evaluated, Table 3 summarizes the adverse reactions in EPCORE NHL-1.24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg. including potential neurology evaluation, and patients at increased risk RECOMMENDED DOSAGE: EPKINLY is for subcutaneous injection only.should be advised not to drive and to refrain from operating heavy orTable 3: Adverse Reactions ( 10%) in Patients with Relapsed or Administer EPKINLY in 28-day cycles until disease progression or potentially dangerous machinery until resolution. Refractory LBCL Who Received EPKINLY in EPCORE NHL-1unacceptable toxicity. Table 1:EPKINLY 2-step up Dosage Schedule forInfections EPKINLYPatients with DLBCL or High-grade B-cell Lymphoma: Cycle 1, day 1:EPKINLY can cause serious and fatal infections. (N=157)EPKINLY 0.16 mg (step-up dose 1); day 8: EPKINLY 0.8 mg (step-up doseSerious infections, including opportunistic infections, were reported in 15%Adverse ReactionAll Grades Grade 3 or 4 2); day 15: EPKINLY 48 mg (first full dose); day 22: EPKINLY 48 mg; Cyclesof patients with LBCL receiving EPKINLY at the recommended 2-step up(%) (%)2 and 3, days 1, 8, 15, and 22: EPKINLY 48 mg; Cycles 4 to 9, days 1 anddosage schedule in EPCORE NHL-1 and were most commonly due to sepsis 15: EPKINLY 48 mg; Cycle 10 and beyond, day 1: EPKINLY 48 mg. Table 2: (4.5%) and pneumonia (3.2%). Fatal infections occurred in 1.3% of patientsImmune system disordersEPKINLY 3-step up Dosage Schedule for Patients with FL: Cycle 1, day 1:and included COVID-19 (1.3%).Cytokine release syndrome* 51 2.5#EPKINLY 0.16 mg (step-up dose 1); day 8: EPKINLY 0.8 mg (step-up dose 2); day 15:EPKINLY 3 mg (step-up dose 3); day 22:EPKINLY 48 mg (first fullSerious infections, including opportunistic infections, were reported inGeneral disorders and administration site conditionsdose); Cycles 2 and 3, days 1, 8, 15, and 22:EPKINLY 48 mg; Cycles 4 to 9, 40% of patients with FL receiving EPKINLY following the 2-step up dosageFatiguea 29 2.5#days 1 and 15: EPKINLY 48 mg; Cycle 10 and beyond, day 1: EPKINLY 48 mg. schedule in EPCORE NHL-1 and were most commonly due to COVID-19 CONTRAINDICATIONS:None. (20%), pneumonia (13%), and urinary tract infections (3%). Fatal infectionsInjection site reactionsb 27 0occurred in 6% of patients and included COVID-19 (5%), pneumonia (0.8%),Pyrexia 24 0WARNINGS AND PRECAUTIONS and sepsis (0.8%). Cytokine Release Syndrome:EPKINLY can cause CRS, including serious Monitor patients for signs and symptoms of infection prior to and duringEdemac 14 1.9#or life-threatening reactions. treatment with EPKINLY and treat appropriately. Avoid administration ofMusculoskeletal and connective tissue disordersRelapsed or Refractory Large B-cell Lymphoma (LBCL) EPKINLY in patients with active infections. Provide PJP prophylaxis prior toMusculoskeletal paind 28 1.3#CRS occurred in 51% of patients with LBCL receiving EPKINLY at theinitiating treatment with EPKINLY; consider initiating prophylaxis against recommended 2-step up dosage schedule in EPCORE NHL, with Grade 1herpes virus prior to starting EPKINLY. Gastrointestinal disorders CRS occurring in 37%, Grade 2 in 17%, and Grade 3 in 2.5% of patients.Withhold or consider permanent discontinuation of EPKINLY based onAbdominal paine 23 1.9#Recurrent CRS occurred in 16% of patients. Of all the CRS events, mostseverity. Diarrhea 20 0(92%) occurred during Cycle 1. In Cycle 1, 9% of CRS events occurredCytopenias #after the 0.16 mg dose on Cycle 1 Day 1, 16% after the 0.8 mg dose onNausea 20 1.3Cycle 1 Day 8, 61% after the 48 mg dose on Cycle 1 Day 15, and 6% afterEPKINLY can cause serious or severe cytopenias, including neutropenia,Vomiting 12 0.6#the 48 mg dose on Cycle 1 Day 22. The median time to onset of CRS fromanemia, and thrombocytopenia.the most recent administered EPKINLY dose across all doses was 24 hoursAmong LBCL patients who received EPKINLY at the recommended 2-stepSkin and subcutaneous disorders(range: 0 to 10 days). The median time to onset after the first full 48 mgup dosage schedule in EPCORE NHL-1, Grade3 or 4 decreased neutrophilsRashf 15 0.6#dose was 21 hours (range: 0 to 7 days). CRS resolved in 98% of patientsoccurred in 32%, decreased hemoglobin in 12%, and decreased platelets in and the median duration of CRS events was 2 days (range: 1 to 27 days).12% of patients. Febrile neutropenia occurred in 2.5%. In patients with FLNervous system disorderPatients with DLBCL or high-grade B-cell lymphoma should be hospitalizedwho received EPKINLY following the 2-step up dosage schedule in EPCOREHeadache 13 0.6#for 24 hours following administration of the first full 48 mg dose. NHL-1, Grade 3 or 4 decreased neutrophils occurred in 30%, decreasedMetabolism and nutrition disordersRelapsed or Refractory Follicular Lymphoma (FL) hemoglobin in 10%, and decreased platelets in 8% of patients. Febrile CRS occurred in 49% (42/86) of patients with FL receiving EPKINLY at theneutropenia occurred in 3.1%. Decreased appetite 12 0.6#recommended 3-step up dosage schedule in EPCORE NHL-1, with Grade1Monitor complete blood counts throughout treatment. Based on the severityCardiac disordersCRS occurring in 45% and Grade2 in 9% of patients. Recurrent CRS of cytopenias, temporarily withhold or permanently discontinue EPKINLY.Cardiac arrhythmiasg 10 0.6#occurred in 23% of patients. Of all the CRS events, most (88%) occurredConsider prophylactic granulocyte colony-stimulating factor administration during Cycle1. In Cycle1, 14% of CRS events occurred after the 0.16mgas applicable. # Adverse reactions were graded based on CTCAE Version 5.0dose on Cycle1 Day1, 7% after the 0.8mg dose on Cycle1 Day8, 17%Only grade 3 adverse reactions occurred.after the 3mg dose on Cycle1 Day15, and 49% after the 48mg dose onEmbryo-Fetal Toxicity * CRS was graded using ASTCT consensus criteria (Lee et al., 2019).Cycle1 Day22. The median time to onset of CRS from the most recentBased on its mechanism of action, EPKINLY may cause fetal harm whenaFatigue includes asthenia, fatigue, lethargy.administered EPKINLY dose across all doses was 59hours (range: 0.1administered to a pregnant woman. Advise pregnant women of the potentialbInjection site reactions includes injection site erythema, injection site to 7days). The median time to onset after the first full 48mg dose wasrisk to the fetus. Advise females of reproductive potential to use effectivehypertrophy, injection site inflammation, injection site mass, injection 61hours (range: 0.1 to 7days). CRS resolved in 100% of patients and thecontraception during treatment with EPKINLY and for 4months after thesite pain, injection site pruritus, injection site rash, injection site reaction, median duration of CRS events was 2days (range: 1 to 14days).last dose. c injection site swelling, injection site urticaria.Edemaincludes edema, edema peripheral, face edema, generalized In both patients with LBCL and FL who experienced CRS, the signs andADVERSE REACTIONS edema, peripheral swelling.symptoms included pyrexia, hypotension, hypoxia, dyspnea, chills, andClinical Trials Experience dMusculoskeletal pain includes back pain, bone pain, flank pain, tachycardia. Concurrent neurological adverse reactions associated withBecause clinical trials are conducted under widely varying conditions,musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, CRS occurred in 2.5% of patients with LBCL and 4.7% of patients withadverse reaction rates observed in the clinical trials of a drug cannot bee non-cardiac chest pain, pain, pain in extremity, spinal pain.FL. Concurrent neurological adverse reactions observed in patients withdirectly compared to rates in the clinical trials of another drug and may notAbdominal pain includes abdominal discomfort, abdominal pain,LBCL included headache, confusional state, tremors, dizziness, and ataxia.reflect the rates observed in practice. f abdominal pain lower, abdominal pain upper, abdominal tenderness.Concurrent neurological adverse reactions observed in patients with FLRash includes dermatitis bullous, erythema, palmar erythema, penile included headache and dizziness. Relapsed or Refractory Large B-cell Lymphoma (LBCL) erythema, rash, rash erythematous, rash maculo-papular, rash pustular, Initiate therapy according to EPKINLY step-up dosage schedule. AdministerEPCORE NHL-1 g recall phenomenon, seborrheic dermatitis, skin exfoliation.pretreatment medications to reduce the risk of CRS and monitor patients forThe safety of EPKINLY was evaluated in EPCORE NHL-1, a single-armCardiac arrhythmias includes bradycardia, sinus bradycardia, sinus potential CRS following EPKINLY accordingly. At the first signs or symptomsstudy of patients with relapsed or refractory LBCL after two or more linestachycardia, supraventricular extrasystoles, supraventricular tachycardia, of CRS, immediately evaluate patients for hospitalization, manage perof systemic therapy, including DLBCL not otherwise specified, DLBCLtachycardia.8THEDIRECTORY VISN'