EPKINLY

1 INDICATIONS AND USAGE EPKINLY is a bispecific CD20-directed CD3 T-cell engager indicated: For the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy. ( 1.1 ) This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). In combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL). ( 1.2 ) As monotherapy for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy. ( 1.2 ) 1.1 DLBCL and High-grade B-cell Lymphoma EPKINLY is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14.1) ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 1.2 Follicular Lymphoma EPKINLY is indicated in combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL). EPKINLY is indicated as monotherapy for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.

2 DOSAGE AND ADMINISTRATION For subcutaneous injection only. ( 2.2 ) Recommended Dosage: ( 2.2 ) DLBCL and High-grade B-cell Lymphoma Cycle Cycle = 28 days Day Dose of EPKINLY Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 First full dose 48 mg 22 48 mg Cycles 2 and 3 1, 8, 15 and 22 48 mg Cycles 4 to 9 1 and 15 48 mg Cycle 10 and beyond 1 48 mg EPKINLY as Monotherapy for FL Cycle Cycle = 28 days Day Dose of EPKINLY Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 Step-up dose 3 3 mg 22 First full dose 48 mg Cycles 2 and 3 1, 8, 15 and 22 48 mg Cycles 4 to 9 1 and 15 48 mg Cycle 10 and beyond 1 48 mg EPKINLY in Combination with Lenalidomide and Rituximab for FL Cycle Cycle = 28 days Day Dose of EPKINLY Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 Step-up dose 3 3 mg 22 First full dose 48 mg Cycles 2 and 3 1, 8, 15, and 22 48 mg Cycles 4 to 12 1 48 mg Monitor all patients for signs and symptoms of CRS and ICANS. ( 2.1 ) For patients with DLBCL or high-grade B-cell lymphoma, assess whether hospitalization or outpatient monitoring is appropriate after administration of the Cycle 1 Day 15 dosage of 48 mg. ( 2.1 ) For patients with FL, assess whether hospitalization or outpatient monitoring is appropriate after administration of the Cycle 1 Day 22 dosage of 48 mg. ( 2.1 ) Administer premedications, post-medications, and prophylaxis as recommended. ( 2.4 , 2.5 ) Dosages of EPKINLY 0.16 mg and 0.8 mg require dilution prior to administration. ( 2.7 , 2.8 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.7 , 2.8 , 2.9 , 2.10 ) 2.1 Important Dosing Information Certain doses of EPKINLY require dilution prior to administration. There are 2 available methods to prepare diluted EPKINLY: Empty sterile vial method as described in subsection 2.7 [see Dosage and Administration (2.7) ] , or Sterile syringe method as described in subsection 2.8 [see Dosage and Administration (2.8) ] . Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution. [see Dosage and Administration (2.9) ] . EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS [see Warnings and Precautions (5.1 , 5.2) ] . Administer EPKINLY to well-hydrated patients. Premedicate before each dose in Cycle 1 [see Dosage and Administration (2.4) ] . Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS [see Dosage and Administration (2.2) ] . Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms [see Dosage and Administration (2.6) ] . Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the first 48 mg dosage of EPKINLY for patients with: DLBCL or high-grade B-cell lymphoma: on Cycle 1 Day 15 [see Dosage and Administration (2.2) ]. FL: on Cycle 1 Day 22 [see Dosage and Administration (2.2) ]. 2.2 Recommended Dosage EPKINLY is for subcutaneous injection only. The recommended DLBCL dosage for Cycle 1 consists of 2 step-up doses, and the recommended FL dosage (monotherapy or in combination with lenalidomide and rituximab) consists of 3 step-up doses. EPKINLY as Monotherapy: Administer EPKINLY in 28-day cycles until disease progression or unacceptable toxicity. Table 1: EPKINLY Dosage Schedule for Patients with DLBCL or High-grade B-cell Lymphoma Indication Cycle Cycle = 28 days. Day Dose of EPKINLY DLBCL or High-grade B-cell Lymphoma Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 First full dose 48 mg 22 48 mg Cycles 2 and 3 1, 8, 15 and 22 48 mg Cycles 4 to 9 1 and 15 48 mg Cycle 10 and beyond 1 48 mg Table 2: EPKINLY Dosage Schedule for Patients with FL when Given as Monotherapy Indication Cycle Cycle = 28 days. Day Dose of EPKINLY Follicular Lymphoma Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 Step-up dose 3 3 mg 22 First full dose 48 mg Cycles 2 and 3 1, 8, 15 and 22 48 mg Cycles 4 to 9 1 and 15 48 mg Cycle 10 and beyond 1 48 mg EPKINLY in Combination with Lenalidomide and Rituximab: Administer EPKINLY in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurs first. Table 3: EPKINLY Dosage Schedule in Combination with Lenalidomide and Rituximab for Patients with FL Indication Cycle Cycle = 28 days. Day Dose of EPKINLY Follicular Lymphoma Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 Step-up dose 3 3 mg 22 First full dose 48 mg Cycles 2 and 3 1, 8, 15, and 22 48 mg Cycles 4 to 12 1 48 mg Administer EPKINLY in combination with lenalidomide 20 mg (Days 1 to 21 in Cycles 1 to 12) and rituximab 375 mg/m 2 (Cycles 1 to 5) [see Clinical Studies (14.2) ]. Refer to the lenalidomide prescribing information and rituximab prescribing information for the respective dosage recommendations, including lenalidomide dosage recommendations for patients with renal insufficiency. 2.3 Restarting EPKINLY after Dosage Delay If a dose of EPKINLY is delayed, restart therapy based on the recommendations made in Table 4 for patients with DLBCL or high-grade B-cell lymphoma, or Table 5 for patients with FL [see Dosage and Administration (2.2) ] . Table 4: Recommendations for Restarting EPKINLY After Dosage Delay for Patients with DLBCL or High-grade B-cell Lymphoma Last Dose Administered Time Since the Last Dose Administered Action for Next Dose(s) Administer pretreatment medication prior to EPKINLY dose and monitor patients accordingly [see Dosage and Administration (2.4 , 2.6) ]. 0.16 mg (e.g., on Cycle 1 Day 1) More than 8 days Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. 0.8 mg (e.g., on Cycle 1 Day 8) 14 days or less Administer 48 mg, then resume the planned treatment schedule. More than 14 days Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. 48 mg (e.g., on Cycle 1 Day 15 onwards) 6 weeks or less Administer 48 mg, then resume the planned treatment schedule. More than 6 weeks Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. Table 5: Recommendations for Restarting EPKINLY After Dosage Delay for Patients with FL Last Dose Administered Time Since the Last Dose Administered Action for Next Dose(s) Administer pretreatment medication prior to EPKINLY dose and monitor patients accordingly [see Dosage and Administration (2.4 , 2.6) ]. 0.16 mg (e.g., on Cycle 1 Day 1) More than 8 days Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. 0.8 mg (e.g., on Cycle 1 Day 8) More than 8 days Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. 3 mg (e.g., on Cycle 1 Day 15) 14 days or less Administer 48 mg, then resume the planned treatment schedule. More than 14 days Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. 48 mg (e.g., on Cycle 1 Day 22 onwards) 6 weeks or less Administer 48 mg, then resume the planned treatment schedule. More than 6 weeks Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. 2.4 Recommended Pre- and Post-Administration Medications Administer pre- and post-administration medications as outlined in Table 6 to reduce the risk of CRS [see Warnings and Precautions (5.1) ] . Table 6: EPKINLY Pre- and Post-Administration Medications Cycle Patients requiring medication Medication Administration Cycle 1 All patients Dexamethasone Dexamethasone is the preferred corticosteroid when available. (15 mg oral or intravenous) or Prednisolone (100 mg oral or intravenous) or equivalent 30-120 minutes prior to each weekly administration of EPKINLY And for three consecutive days following each weekly administration of EPKINLY in Cycle 1 Diphenhydramine (50 mg oral or intravenous) or equivalent Acetaminophen (650 mg to 1,000 mg oral) 30-120 minutes prior to each weekly administration of EPKINLY Cycle 2+ Patients who experienced Grade 2 or 3 Patients will be permanently discontinued from EPKINLY after Grade 4 CRS. CRS with previous dose Dexamethasone (15 mg oral or intravenous) or Prednisolone (100 mg oral or intravenous) or equivalent 30-120 minutes prior to next administration of EPKINLY after a Grade 2 or 3 CRS event And for three consecutive days following the next administration of EPKINLY until EPKINLY is given without subsequent CRS of Grade 2 or higher 2.5 Recommended Prophylaxis Pneumocystis jirovecii pneumonia (PJP) Provide PJP prophylaxis during treatment with EPKINLY. Herpesvirus Consider providing prophylaxis against herpesvirus during treatment with EPKINLY to prevent herpes simplex and herpes zoster. Thromboprophylaxis Refer to the lenalidomide prescribing information for recommendations on prophylaxis for venous and arterial thrombotic events. 2.6 Dosage Modifications and Management of Adverse Reactions See Tables 7 and 8 for recommended actions for adverse reactions of CRS and ICANS, respectively. See Tables 9 and 10 for recommended actions for other adverse reactions following administration of EPKINLY given as monotherapy and in combination with lenalidomide and rituximab, respectively. Cytokine Release Syndrome (CRS) Identify CRS based on clinical presentation [see Warnings and Precautions (5.1) ] . Evaluate for and treat other causes of fever, hypotension, and hypoxia. If CRS is suspected, withhold EPKINLY until CRS resolves. Manage according to the recommendations in Table 7 and consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS. Table 7: Recommendations for Management of Cytokine Release Syndrome Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS. Presenting Symptoms Actions Grade 1 Temperature ≥ 100.4°F (38°C) Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow these management guidelines. Withhold EPKINLY and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of EPKINLY. Refer to Table 4 or Table 5 for information on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3) ] . Grade 2 Temperature ≥ 100.4°F (38°C) with: Hypotension not requiring vasopressors and/or Hypoxia requiring low-flow oxygen Low-flow oxygen defined as oxygen delivered at < 6L/minute; high-flow oxygen defined as oxygen delivered at ≥ 6 L/minute. by nasal cannula or blow-by. Withhold EPKINLY and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of EPKINLY. Administer premedication If Grade 2 or 3 CRS occurs with the second full dose (48 mg) or beyond, administer CRS pre- and post-administration medications with each subsequent dose until a EPKINLY dose is given without subsequent CRS of Grade 2 or higher. Refer to Table 6 for additional information on pre- and post-administration medications. prior to next dose of EPKINLY. For the next dose of EPKINLY, monitor more frequently and consider hospitalization. Grade 3 Temperature ≥ 100.4°F (38°C) with: Hypotension requiring a vasopressor (with or without vasopressin) and/or Hypoxia requiring high-flow oxygen by nasal cannula, face mask, non-rebreather mask, or Venturi mask. Withhold EPKINLY and manage per current practice guidelines, which may include intensive care. Ensure CRS symptoms are resolved prior to the next dose of EPKINLY. Administer premedication prior to next dose of EPKINLY. Hospitalize for the next dose of EPKINLY. Recurrent Grade 3 CRS Permanently discontinue EPKINLY. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care. Grade 4 Temperature ≥ 100.4°F (38°C) with: Hypotension requiring multiple vasopressors (excluding vasopressin) and/or Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation). Permanently discontinue EPKINLY. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care. Immune Effector Cell-Associated Neurological Toxicity Syndrome (ICANS) Monitor patients for signs and symptoms of ICANS [see Warnings and Precautions (5.2) ] . At the first sign of ICANS, withhold EPKINLY and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for ICANS [see Warnings and Precautions (5.2) ]. Manage ICANS according to the recommendations in Table 8 and consider further management per current practice guidelines. Table 8: Recommendations for Management of Immune Effector Cell-Associated Neurotoxicity Syndrome Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS. Presenting Symptoms Management is determined by the most severe event, not attributable to any other cause. Actions Grade 1 ICE score 7-9 If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (names 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., "show me 2 fingers" or "close your eyes and stick out your tongue" = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points. , Or depressed level of consciousness Not attributable to any other cause. : awakens spontaneously. Withhold EPKINLY until ICANS resolves. See Table 4 or Table 5 for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3) ]. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Grade 2 ICE score 3-6 , Or depressed level of consciousness : awakens to voice. Withhold EPKINLY until ICANS resolves. Administer dexamethasone All references to dexamethasone administration are dexamethasone or equivalent. 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Grade 3 ICE score 0-2 , Or depressed level of consciousness : awakens only to tactile stimulus, Or seizures, either: Any clinical seizure, focal or generalized, that resolves rapidly, or Non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, Or raised intracranial pressure: focal/local edema on neuroimaging. First Occurrence of Grade 3 ICANS Withhold EPKINLY until ICANS resolves. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care. Recurrent Grade 3 ICANS Permanently discontinue EPKINLY Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care. Grade 4 ICE score 0 , Or depressed level of consciousness : either: Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or Stupor or coma Or seizures, either: Life-threatening prolonged seizure (> 5 minutes), or Repetitive clinical or electrical seizures without return to baseline in between, Or motor findings : Deep focal motor weakness, such as hemiparesis or paraparesis, or raised intracranial pressure/cerebral edema, with signs/symptoms such as: Diffuse cerebral edema on neuroimaging, or Decerebrate or decorticate posturing, or Cranial nerve VI palsy, or Papilledema, or Cushing's triad. Permanently discontinue EPKINLY. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Alternatively, consider administration of methylprednisolone 1,000 mg per day intravenously and continue methylprednisolone 1,000 mg per day intravenously for 2 or more days. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care. Table 9: Recommended Dosage Modifications for Other Adverse Reactions when EPKINLY is Given as Monotherapy Adverse Reaction Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. Severity Action Infections [see Warnings and Precautions (5.3) ] Grades 1-4 Withhold EPKINLY in patients with active infection, until the infection resolves. See Table 4 or Table 5 for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3) ]. For Grade 4, consider permanent discontinuation of EPKINLY. Neutropenia [see Warnings and Precautions (5.4) ] Absolute neutrophil count less than 0.5 × 10 9 /L Withhold EPKINLY until absolute neutrophil count is 0.5 × 10 9 /L or higher. Thrombocytopenia [see Warnings and Precautions (5.4) ] Platelet count less than 50 × 10 9 /L Withhold EPKINLY until platelet count is 50 × 10 9 /L or higher. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 or higher Withhold EPKINLY until the toxicity resolves to Grade 1 or baseline. Table 10: Recommended Dosage Modifications for Other Adverse Reactions when EPKINLY is Given in Combination with Lenalidomide and Rituximab Adverse Reaction Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. Action Refer to lenalidomide prescribing information for additional toxicity guidelines. Neutropenia [see Warnings and Precautions (5.4) ] Absolute neutrophil count less than 0.5 × 10 9 /L Consider G-CSF. Withhold EPKINLY until absolute neutrophil count is 1 × 10 9 /L or higher. See Table 4 or 5 for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3) ]. Withhold lenalidomide for remainder of cycle. On Day 1 of next cycle, the dose of lenalidomide may be maintained if neutropenia was the only toxicity limiting lenalidomide dosing. Febrile Neutropenia [see Warnings and Precautions (5.4) ] Grade 3 or higher Consider G-CSF. Withhold EPKINLY until fever resolves and absolute neutrophil count is 1 × 10 9 /L or higher. Withhold lenalidomide for remainder of cycle. On Day 1 of next cycle, dose of lenalidomide may be maintained if febrile neutropenia was the only toxicity limiting lenalidomide dosing. Thrombocytopenia [see Warnings and Precautions (5.4) ] Platelet count less than 50 × 10 9 /L Withhold EPKINLY until platelet count is 50 × 10 9 /L or higher. Withhold lenalidomide for remainder of cycle. Decrease lenalidomide dose for next cycle. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 For first episode, withhold EPKINLY until improvement to Grade 2 or less or resolution to baseline. For second episode, permanently discontinue EPKINLY if clinically indicated. Grade 4 Permanently discontinue EPKINLY at discretion of healthcare provider. 2.7 Preparation of Diluted EPKINLY using the Vial Method Read this entire section carefully before preparation of EPKINLY. Certain doses of EPKINLY require dilution prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to improper dose. This section describes preparation of diluted EPKINLY using empty sterile vial method. For preparation using sterile syringe method, see subsection 2.8 [see Dosage and Administration (2.8) ] . EPKINLY is prepared and administered by a healthcare provider as a subcutaneous injection. The administration of EPKINLY takes place over the course of 28-day cycles, following the step-up dosage schedule in Section 2.2. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique to prepare EPKINLY. Filtration of the diluted solution is not required. 0.16 mg Dose Preparation Instructions ( 2 dilutions required ) – Empty Sterile Vial Method Use an appropriately sized syringe, vial, and needle for each transfer step. 1. Prepare EPKINLY vial a. Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator. b. Allow the vial to come to room temperature for no more than 1 hour. c. Gently swirl the EPKINLY vial. DO NOT invert, vortex, or vigorously shake the vial. 2. Perform first dilution a. Label an appropriately sized empty vial as "Dilution A." b. Transfer 0.8 mL of EPKINLY into the Dilution A vial. c. Transfer 4.2 mL of 0.9% Sodium Chloride Injection into the Dilution A vial. The initially diluted solution contains 0.8 mg/mL of EPKINLY. d. Gently swirl the Dilution A vial for 30 to 45 seconds. 3. Perform second dilution a. Label an appropriately sized empty vial as "Dilution B." b. Transfer 2 mL of solution from the Dilution A vial into the Dilution B vial. The Dilution A vial is no longer needed. c. Transfer 8 mL of 0.9% Sodium Chloride Injection into the Dilution B vial to make a final concentration of 0.16 mg/mL. d. Gently swirl the Dilution B vial for 30 to 45 seconds. 4. Withdraw dose a. Withdraw 1 mL of the diluted EPKINLY from the Dilution B vial into a syringe. 5. Label syringe a. Label the syringe with the dose strength (0.16 mg) and the time of day. Discard the vial containing unused EPKINLY. 0.8 mg Dose Preparation Instructions ( 1 dilution required ) – Empty Sterile Vial Method Use an appropriately sized syringe, vial, and needle for each transfer step. 1. Prepare EPKINLY vial a. Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator. b. Allow the vial to come to room temperature for no more than 1 hour. c. Gently swirl the EPKINLY vial. DO NOT invert, vortex, or vigorously shake the vial. 2. Perform dilution a. Label an appropriately sized empty vial as " Dilution A ". b. Transfer 0.8 mL of EPKINLY into the Dilution A vial. c. Transfer 4.2 mL of 0.9% Sodium Chloride Injection into the Dilution A vial to make a final concentration of 0.8 mg/mL. d. Gently swirl the Dilution A vial for 30 to 45 seconds. 3. Withdraw dose a. Withdraw 1 mL of the diluted EPKINLY from the Dilution A vial into a syringe. 4. Label syringe a. Label the syringe with the dose strength (0.8 mg) and the time of day. Discard the vial containing unused EPKINLY. 2.8 Preparation of Diluted EPKINLY using the Syringe Method Read this entire section carefully before preparation of EPKINLY. Certain doses of EPKINLY require dilution prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to improper dose. EPKINLY is prepared and administered by a healthcare provider as a subcutaneous injection. The administration of EPKINLY takes place over the course of 28-day cycles, following the step-up dosage schedule in Section 2.2. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique to prepare EPKINLY. Filtration of the diluted solution is not required. 0.16 mg Dose Preparation Instructions ( 2 dilutions required ) – Sterile Syringe Method Use an appropriately sized syringe and needle for each transfer step. 1. Prepare EPKINLY vial a. Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator. b. Allow the vial to come to room temperature for no more than 1 hour. c. Gently swirl the EPKINLY vial. DO NOT invert, vortex, or vigorously shake the vial. 2. Perform first dilution a. Label an appropriately sized syringe as "Dilution A." b. Withdraw 4.2 mL of 0.9% Sodium Chloride Injection into the Dilution A syringe. Include approximately 0.2 mL air in the syringe. c. In a new syringe labeled as "Syringe 1" , withdraw 0.8 mL of EPKINLY . d. Connect the two syringes and push the 0.8 mL of EPKINLY into the Dilution A syringe. The initially diluted solution contains 0.8 mg/mL of EPKINLY e. Gently mix by inverting the connected syringes 180 degrees 5 times. f. Disconnect the syringes and discard Syringe 1 . 3. Perform second dilution a. Label an appropriately sized syringe as "Dilution B." b. Withdraw 8 mL of 0.9% Sodium Chloride Injection into the Dilution B syringe. Include approximately 0.2 mL air in the syringe. c. Label another appropriately sized syringe as "Syringe 2." d. Connect Syringe 2 to the Dilution A syringe and transfer 2 mL of solution into Syringe 2 . The Dilution A syringe is no longer needed. e. Connect Syringe 2 to the Dilution B syringe and push the 2 mL of solution into the Dilution B syringe to make a final concentration of 0.16 mg/mL. f. Gently mix by inverting the connected syringes 180 degrees 5 times. g. Disconnect the syringes and discard Syringe 2 . 4. Withdraw dose a. Connect and transfer 1 mL of the diluted EPKINLY from the Dilution B syringe into a new syringe. The Dilution B syringe is no longer needed. 5. Label syringe a. Label the syringe with the dose strength (0.16 mg) and the time of day. Discard the vial containing unused EPKINLY. 0.8 mg Dose Preparation Instructions ( 1 dilution required ) – Sterile Syringe Method Use an appropriately sized syringe and needle for each transfer step. 1. Prepare EPKINLY vial a. Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator. b. Allow the vial to come to room temperature for no more than 1 hour. c. Gently swirl the EPKINLY vial. DO NOT invert, vortex, or vigorously shake the vial. 2. Perform dilution a. Label an appropriately sized syringe as "Dilution A." b. Withdraw 4.2 mL of 0.9% Sodium Chloride Injection into the Dilution A syringe. Include approximately 0.2 mL air in the syringe. c. In a new syringe labeled as " Syringe 1 ", withdraw 0.8 mL of EPKINLY . d. Connect the two syringes and push the 0.8 mL of EPKINLY into the Dilution A syringe to make a final concentration of 0.8 mg/mL. e. Gently mix by inverting the connected syringes 180 degrees 5 times. f. Disconnect the syringes and discard Syringe 1 . 3. Withdraw dose a. Connect a new syringe to the Dilution A syringe and transfer 1 mL of the diluted EPKINLY into the new syringe. The Dilution A syringe is no longer needed. 4. Label syringe a. Label the syringe with the dose strength (0.8 mg) and the time of day. Discard the vial containing unused EPKINLY. 2.9 Preparation of 3 mg and 48 mg EPKINLY Doses Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique to prepare EPKINLY. 3 mg Dose Preparation Instructions (No dilution required) EPKINLY 3 mg dose is required for patients with FL only [see Dosage and Administration (2.2) ] . 1. Prepare EPKINLY vial a. Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator. b. Allow the vial to come to room temperature for no more than 1 hour. c. Gently swirl the EPKINLY vial. DO NOT invert, vortex, or vigorously shake the vial. 2. Withdraw dose a. Withdraw 0.6 mL of EPKINLY into a syringe. 3. Label syringe a. Label the syringe with the dose strength (3 mg) and the time of day. Discard the vial containing unused EPKINLY. 48 mg Dose Preparation Instructions ( No dilution required ) EPKINLY 48 mg/0.8 mL vial is supplied as ready-to-use solution that does not need dilution prior to administration. 1. Prepare EPKINLY vial a. Retrieve one 48 mg/0.8 mL EPKINLY vial from the refrigerator. b. Allow the vial to come to room temperature for no more than 1 hour. c. Gently swirl the EPKINLY vial. DO NOT invert, vortex, or vigorously shake the vial. 2. Withdraw dose a. Withdraw 0.8 mL of EPKINLY into a syringe. 3. Label syringe a. Label the syringe with the dose strength (48 mg) and the time of day. Discard the vial containing unused EPKINLY. 2.10 Storage and Administration Storage of EPKINLY Solution in the Syringe Use EPKINLY solution in the syringe immediately. If not used immediately, store the solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at room temperature at 20°C to 25°C (68°F to 77°F) for up to 12 hours. The total storage time from the start of dose preparation to administration should not exceed 24 hours. Protect from direct sunlight. Discard unused EPKINLY solution beyond the allowable storage time. Administration of EPKINLY To minimize injection pain, allow EPKINLY solution to equilibrate to room temperature for no more than 1 hour before administration. Inject the required volume of EPKINLY into the subcutaneous tissue of the lower part of the abdomen (preferred injection site) or the thigh. Change of injection site from the left or right side or vice versa is recommended, especially during the weekly administrations (Cycles 1 to 3). Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, or not intact.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Infections: Can cause fatal or serious infections. Monitor patients for signs or symptoms of infection, including opportunistic infections, and treat appropriately. ( 5.3 ) Cytopenias: Monitor complete blood cell counts during treatment. ( 5.4 ) Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 Cytokine Release Syndrome EPKINLY can cause CRS, including serious or fatal reactions [see Adverse Reactions (6.1) ] . Relapsed or Refractory Large B-cell Lymphoma CRS occurred in 51% (80/157) of patients with LBCL receiving EPKINLY at the recommended dosage schedule in EPCORE NHL-1, with Grade 1 CRS occurring in 37%, Grade 2 in 17%, and Grade 3 in 2.5% of patients. Recurrent CRS occurred in 31% of these patients. Most CRS events (92%) occurred during Cycle 1. In Cycle 1, CRS events occurred in 6% of patients after the 0.16 mg dose, 12% after the 0.8 mg dose, 43% after the first 48 mg dose, and 5% after the next 48 mg dose. The median time to onset of CRS from the most recent EPKINLY dose was 24 hours (range: 0 to 10 days). The median time to onset after the first 48 mg dose was 21 hours (range: 0 to 7 days). For patients with LBCL, assess whether hospitalization or outpatient monitoring for the first 48 mg dose (Cycle 1 Day 15) is appropriate based on comorbidities or other situational factors [see Dosage and Administration (2.1) ]. During outpatient monitoring after the first 48 mg dose, patients should remain in proximity to a healthcare facility that can assess and manage CRS. Relapsed or Refractory Follicular Lymphoma CRS occurred in 49% (42/86) of patients with FL receiving EPKINLY monotherapy at the recommended dosage schedule in EPCORE NHL-1, with Grade 1 CRS occurring in 45% and Grade 2 in 9% of patients. Recurrent CRS occurred in 48% of patients. Most CRS events (88%) occurred during Cycle 1. In Cycle 1, CRS events occurred in 12% of patients after the 0.16 mg dose, 6% after the 0.8 mg dose, 15% after the 3 mg dose, and 37% after the first 48 mg dose. The median time to onset of CRS from the most recent EPKINLY dose was 59 hours (range: 0.1 to 7 days). The median time to onset after the first 48 mg dose was 61 hours (range: 0.1 to 7 days). CRS occurred in 24% (32/131) of patients with FL receiving EPKINLY at the recommended dosage schedule in combination with lenalidomide and rituximab in EPCORE FL-1, with Grade 1 CRS occurring in 19%, Grade 2 in 5% of patients, and serious adverse reactions due to CRS in 12%. Recurrent CRS occurred in 41% of patients. Most CRS events (88%) occurred during Cycle 1. In Cycle 1, CRS occurred in 5% of patients after the 0.16 mg dose, 3.8% after the 0.8 mg dose, 2.3% after the 3 mg dose, and 18% after the first 48 mg dose. The median time to onset of CRS from the most recent EPKINLY dose was 78 hours (range: 0.2 to 12 days). The median time to onset after the first 48 mg dose was 41 hours (range: 0.3 to 12 days). For patients with FL, assess whether hospitalization or outpatient monitoring for the first 48 mg dose (Cycle 1 Day 22) is appropriate based on comorbidities or other situational factors [see Dosage and Administration (2.1) ] . During outpatient monitoring after the first 48 mg dose, patients should remain in proximity to a healthcare facility that can assess and manage CRS. Among patients with LBCL or FL who experienced CRS, signs and symptoms included pyrexia, hypotension, hypoxia, dyspnea, chills, and tachycardia. CRS resolved in 98% of patients, after a median duration of 2 days (range: < 1 to 27 days). Concurrent neurological adverse reactions associated with CRS occurred in 2.5% of patients with LBCL, 4.7% of patients with FL receiving EPKINLY monotherapy, and 1.5% of patients receiving EPKINLY in combination with lenalidomide and rituximab. Concurrent neurological adverse reactions included headache, confusional state, tremors, dizziness, and ataxia. Initiate EPKINLY according to the recommended step-up dosage schedule. Administer pretreatment medications to reduce the risk of CRS and monitor patients for potential CRS accordingly [see Dosage and Administration (2.2 , 2.3 , 2.4) ] . At the first signs or symptoms of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care as appropriate. Withhold or discontinue EPKINLY based on the severity of CRS [see Dosage and Administration (2.6) ] . Patients who experience CRS (or other adverse reactions that impair consciousness) should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution. 5.2 Immune Effector Cell-Associated Neurotoxicity Syndrome EPKINLY can cause life-threatening and fatal immune effector cell-associated neurotoxicity syndrome (ICANS) [see Adverse Reactions (6.1) ] . Relapsed or Refractory Large B-cell Lymphoma ICANS occurred in 6% (10/157) of patients with LBCL receiving EPKINLY at the recommended dosage schedule in EPCORE NHL-1, with Grade 1 ICANS in 4.5% and Grade 2 ICANS in 1.3% of patients. There was one (0.6%) fatal ICANS occurrence. Of the 10 ICANS events, 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 the most recent administration of EPKINLY, the median time to onset of ICANS was 3 days (range: 1 to 13 days). The median duration of ICANS was 4 days (range: 0 to 8 days) with ICANS resolving in 90% of patients with supportive care. Relapsed or Refractory Follicular Lymphoma ICANS occurred in 6% (8/127) of patients with FL receiving EPKINLY monotherapy following the 2-step up dosage schedule in EPCORE NHL-1, with Grade 1 ICANS in 3.9% and Grade 2 ICANS in 2.4% of patients. The median time to onset of ICANS was 22 days (range: 14 to 66 days) from the start of treatment. Relative to the most recent administration of EPKINLY, the median time to onset of ICANS was 3 days (range: 0.4 to 7 days). The median duration of ICANS was 2 days (range: 1 to 7 days) with ICANS resolving in 100% of patients. Among patients with FL who received EPKINLY at the recommended dosage schedule in combination with lenalidomide and rituximab in EPCORE FL-1, ICANS occurred in 0.8% (1/131, Grade 1). For patients with LBCL or FL, clinical manifestations of ICANS included, but were not limited to confusional state, lethargy, tremor, dysgraphia, aphasia, and non-convulsive status epilepticus. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Monitor patients for potential ICANS following EPKINLY. At the first signs or symptoms of ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or discontinue EPKINLY per recommendations and consider further management per current practice guidelines [see Dosage and Administration (2.6) ] . Patients who experience signs or symptoms of ICANS or any other adverse reactions that impair cognition or consciousness should be evaluated, including potential neurology evaluation, and patients at increased risk should be advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution. 5.3 Infections EPKINLY can cause fatal and serious infections [see Adverse Reactions (6.1) ] . Serious infections, including opportunistic infections, were reported in 15% of patients with LBCL receiving EPKINLY at the recommended dosage schedule in EPCORE NHL-1 and were most commonly due to sepsis (4.5%) and pneumonia (3.2%). Fatal infections occurred in 1.3% of patients and were due to COVID-19. Serious infections, including opportunistic infections, were reported in 40% of patients with FL receiving EPKINLY monotherapy following the 2-step up dosage schedule in EPCORE NHL-1 and were most commonly due to COVID-19 (20%), pneumonia (13%), and urinary tract infections (3%). Fatal infections occurred in 6% of patients and included COVID-19 (5%), pneumonia (0.8%), and sepsis (0.8%). Among 243 patients with FL who received EPKINLY in combination with lenalidomide and rituximab in EPCORE FL-1, serious infections occurred in 28% of patients. The most common serious infections were pneumonia (15%), COVID-19 (7%), opportunistic infections (5%) and upper respiratory infections (3.3%). The most common opportunistic infections of any grade were CMV infection (7%) and herpesvirus infection (7%). Progressive multifocal leukoencephalopathy (PML), including fatal cases, has occurred in patients treated with EPKINLY. Across a broader clinical trial population, PML was reported in 0.4% (11/3072) of patients, including in the first-line treatment setting. Of the 11 cases of PML, six resulted in fatal outcomes and one was unresolved at the time of death. Monitor patients for signs and symptoms of infection and treat appropriately. Avoid administration of EPKINLY in patients with active infections. Provide PJP prophylaxis during treatment with EPKINLY, and consider initiating prophylaxis against herpesvirus [see Dosage and Administration (2.5) ]. Withhold or consider permanent discontinuation of EPKINLY based on severity [see Dosage and Administration (2.6) ] . 5.4 Cytopenias EPKINLY can cause serious or severe cytopenias, including neutropenia, lymphopenia, anemia, and thrombocytopenia [see Adverse Reactions (6.1) ] . In patients with LBCL who received EPKINLY at the recommended dosage schedule, Grade 3 or 4 decreased neutrophils occurred in 32% (Grade 4, 14%), decreased hemoglobin in 12% (Grade 4, 0%), and decreased platelets in 12% (Grade 4, 7%) of patients. Febrile neutropenia occurred in 2.5% (Grade 4, 0.6%). In patients with FL who received EPKINLY monotherapy following the 2-step up dosage schedule, Grade 3 or 4 decreased neutrophils occurred in 30% (Grade 4, 17%), decreased hemoglobin in 10% (Grade 4, 0%), and decreased platelets in 8% of patients (Grade 4, 4%). Febrile neutropenia occurred in 3.1% (Grade 4, 0%). In patients with FL who received EPKINLY in combination with lenalidomide and rituximab, Grade 3 or 4 decreased neutrophils occurred in 67% (Grade 4, 41%), decreased lymphocytes in 62% (Grade 4, 13%), decreased hemoglobin in 7%, and decreased platelets in 10% (Grade 4, 4.1%) of patients. Febrile neutropenia occurred in 6% (Grade 4, 2.1%). Monitor complete blood counts throughout treatment. Based on the severity of cytopenias, temporarily withhold or permanently discontinue EPKINLY [see Dosage and Administration (2.6) ]. Consider prophylactic granulocyte colony-stimulating factor administration as applicable. 5.5 Embryo-Fetal Toxicity Based on its mechanism of action, EPKINLY may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with EPKINLY and for 4 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

7 DRUG INTERACTIONS For certain CYP substrates, minimal changes in the concentration may lead to serious adverse reactions. Monitor for toxicity or drug concentrations of such CYP substrates when co-administered with EPKINLY. Epcoritamab-bysp causes release of cytokines [see Clinical Pharmacology (12.2) ] that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates. Increased exposure of CYP substrates is more likely to occur after the first dose of EPKINLY and up to 14 days after the first 48 mg dose, and during and after CRS [see Warnings and Precautions (5.1) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cytokine Release Syndrome [see Warnings and Precautions (5.1) ]. Immune Effector Cell-Associated Neurotoxicity Syndrome [see Warnings and Precautions (5.2) ]. Infections [see Warnings and Precautions (5.3) ]. Cytopenias [see Warnings and Precautions (5.4) ]. EPKINLY as monotherapy for LBCL or FL: The most common (≥ 20%) adverse reactions are CRS, injection site reactions, fatigue, musculoskeletal pain, fever, diarrhea, COVID-19, rash and abdominal pain. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) are decreases in lymphocyte count, neutrophil count, hemoglobin, and platelets. ( 6.1 ) EPKINLY in combination with lenalidomide and rituximab for FL: The most common (≥ 20%) adverse reactions are rash, upper respiratory tract infections, fatigue, injection site reactions, constipation, diarrhea, CRS, pneumonia, COVID-19, and fever. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) are decreased neutrophil count, lymphocyte count, and platelets. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genmab US, Inc. at 1-855-4GENMAB (1-855-443-6622) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory Large B-cell Lymphoma (LBCL) EPCORE NHL-1 The safety of EPKINLY was evaluated in EPCORE NHL-1, a single-arm study of patients with relapsed or refractory LBCL after two or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from indolent lymphoma, high grade B-cell lymphoma, and other B-cell lymphomas [see Clinical Studies (14.1) ] . A total of 157 patients with LBCL received EPKINLY via subcutaneous injection until disease 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 on Days 15 and 22 Cycles 2-3: EPKINLY 48 mg on Days 1, 8, 15, and 22 Cycles 4-9: EPKINLY 48 mg on Days 1 and 15 Cycles 10 and beyond: EPKINLY 48 mg on Day 1 Of the 157 patients treated, the median age was 64 years (range: 20 to 83), 60% were male, and 97% had an ECOG performance status of 0 or 1. Race was reported in 133 (85%) patients; of these patients, 61% were White, 19% were Asian, and 0.6% were Native Hawaiian or Other Pacific Islander. There were no Black or African American or Hispanic or Latino patients treated in the clinical trial as reported. The median number of prior therapies was 3 (range: 2 to 11). The study excluded patients with CNS involvement of lymphoma, allogeneic HSCT or solid organ transplant, an ongoing active infection, and any patients with known impaired T-cell immunity. The median duration of exposure for patients receiving EPKINLY was 5 cycles (range: 1 to 20 cycles). Serious adverse reactions occurred in 54% of patients who received EPKINLY. Serious adverse reactions in ≥ 2% of patients included CRS, infections (including sepsis, COVID-19, pneumonia, and upper respiratory tract infections), pleural effusion, febrile neutropenia, fever, and ICANS. Fatal adverse reactions occurred in 3.8% of patients who received EPKINLY, including COVID-19 (1.3%), hepatotoxicity (0.6%), ICANS (0.6%), myocardial infarction (0.6%), and pulmonary embolism (0.6%). Permanent discontinuation of EPKINLY due to an adverse reaction occurred in 3.8% of patients. Adverse reactions which resulted in permanent discontinuation of EPKINLY included COVID-19, CRS, ICANS, pleural effusion, and fatigue. Dosage interruptions of EPKINLY due to an adverse reaction occurred in 34% of patients who received EPKINLY. Adverse reactions which required dosage interruption in ≥ 3% of patients included CRS, neutropenia, sepsis, and thrombocytopenia. The most common (≥ 20%) adverse reactions were CRS, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets. Table 11 summarizes the adverse reactions in EPCORE NHL-1. Table 11: Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory LBCL Who Received EPKINLY in EPCORE NHL-1 EPKINLY (N=157) Adverse Reaction Adverse reactions were graded based on CTCAE Version 5.0 All Grades (%) Grade 3 or 4 (%) Immune system disorders Cytokine release syndrome CRS was graded using ASTCT consensus criteria (Lee et al., 2019). 51 2.5 Only grade 3 adverse reactions occurred. General disorders and administration site conditions Fatigue Fatigue includes asthenia, fatigue, lethargy. 29 2.5 Injection site reactions Injection site reaction includes injection site erythema, injection site hypertrophy, injection site inflammation, injection site mass, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, injection site urticaria. 27 0 Pyrexia 24 0 Edema Edema includes edema, edema peripheral, face edema, generalized edema, peripheral swelling. 14 1.9 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, spinal pain. 28 1.3 Gastrointestinal disorders Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness. 23 1.9 Diarrhea 20 0 Nausea 20 1.3 Vomiting 12 0.6 Skin and subcutaneous disorders Rash Rash includes dermatitis bullous, erythema, palmar erythema, penile erythema, rash, rash erythematous, rash maculo-papular, rash pustular, recall phenomenon, seborrheic dermatitis, skin exfoliation. 15 0.6 Nervous system disorder Headache 13 0.6 Metabolism and nutrition disorders Decreased appetite 12 0.6 Cardiac disorders Cardiac arrhythmias Cardiac arrhythmias includes bradycardia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia. 10 0.6 Clinically relevant adverse reactions in < 10% of patients who received EPKINLY included ICANS, sepsis, pleural effusion, COVID-19, pneumonia (including pneumonia and COVID-19 pneumonia), tumor flare, febrile neutropenia, upper respiratory tract infections, and tumor lysis syndrome. Table 12 summarizes laboratory abnormalities in EPCORE NHL-1. Table 12: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory LBCL Who Received EPKINLY in EPCORE NHL-1 Laboratory Abnormality Laboratory abnormalities were graded based on CTCAE Version 5.0 EPKINLY The denominator used to calculate the rate varied from 146 to 153 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) Hematology Lymphocyte count decreased 87 77 Hemoglobin decreased 62 12 White blood cells decreased 53 22 Neutrophils decreased 50 32 Platelets decreased 48 12 Chemistry Sodium decreased 56 2.6 Phosphate decreased CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value < Lower Limit of Normal (LLN). 56 N/A Aspartate aminotransferase increased 48 4.6 Alanine aminotransferase increased 45 5.3 Potassium decreased 34 5.3 Magnesium decreased 31 0 Creatinine increased 24 3.3 Potassium increased 21 1.3 Relapsed or Refractory Follicular Lymphoma (FL) EPCORE FL-1 The safety of EPKINLY in combination with lenalidomide and rituximab was evaluated in EPCORE FL-1, an open-label, randomized, multicenter trial that included patients with relapsed or refractory FL after at least one line of systemic therapy [see Clinical Studies (14.2) ] . The study excluded patients with transformed lymphoma, absolute neutrophil count < 1.0 × 10 9 /L, platelet count < 70 × 10 9 /L (or < 50 × 10 9 /L if bone marrow infiltration by lymphoma or splenomegaly), known active infection, creatinine clearance < 50 mL/min, alanine or aspartate transaminase > 3 times the upper limit of normal, and clinically significant cardiovascular disease. Patients were randomized to receive EPKINLY in combination with lenalidomide and rituximab (N=243) or lenalidomide and rituximab alone (N=238). Patients received EPKINLY via subcutaneous injection in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurred first. Of the 243 patients who received EPKINLY, 131 received the recommended 3 step-up dosage schedule. The recommended EPKINLY dosage schedule was: Cycle 1: EPKINLY 0.16 mg on Day 1, 0.8 mg on Day 8, 3 mg on Day 15, and 48 mg on Day 22 Cycles 2-3: EPKINLY 48 mg on Days 1, 8, 15, and 22 Cycles 4-12: EPKINLY 48 mg on Day 1 In both treatment arms, lenalidomide was given orally at a dose of 20 mg once daily from Days 1 to 21 for 12 cycles. Rituximab was administered intravenously at a dose of 375 mg/m 2 on Days 1, 8, 15, and 22 of Cycle 1, followed by administration on Day 1 of Cycles 2 to 5. Safety results are based on all 243 patients who received EPKINLY, with the exception of data for CRS and ICANS which are based on patients who received EPKINLY at the recommended dosage schedule. The median duration of exposure in this arm was 10 cycles for EPKINLY and 9 cycles for lenalidomide. Serious adverse reactions occurred in 51% of these patients, including serious infections in 28% of patients and serious CRS in 12% of patients. Fatal adverse reactions within 60 days of last treatment occurred in 0.8% of patients. Adverse reactions led to permanent discontinuation of EPKINLY in 6% of patients and dose interruption in 75% of patients, with infection as a leading cause. Adverse reactions leading to interruption of EPKINLY in ≥ 5% of patients included respiratory tract infections, CRS, and rash. In the EPKINLY arm, adverse reactions led to lenalidomide dose interruption in 72%, dose reduction in 22%, and permanent discontinuation in 15%. The most common (≥ 20%) adverse reactions in the EPKINLY arm were rash, upper respiratory tract infections, fatigue, injection site reactions, constipation, diarrhea, CRS, pneumonia, COVID-19, and fever. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) were decreases in neutrophil count, lymphocyte count, and platelets. Table 13 summarizes select adverse reactions in EPCORE FL-1. Table 13: Adverse Reactions (≥ 10% All Grade and ≥ 5% Higher) in Patients with Relapsed or Refractory FL Who Received EPKINLY in Combination with Lenalidomide and Rituximab in EPCORE FL-1 Adverse Reaction Adverse reactions were graded using CTCAE Version 5.0. CRS was graded using ASTCT consensus criteria (Lee et al., 2019). EPKINLY + Lenalidomide and Rituximab Lenalidomide and Rituximab All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) This table includes a combination of grouped and ungrouped terms. (N=131) (N=238) Immune system disorders Cytokine release syndrome 24 The frequency of CRS is based on 131 patients who received EPKINLY at the recommended dosage schedule [see Dosage and Administration (2.2) ] . Grade 1 CRS: 19%; Grade 2 CRS: 5%. The frequency of CRS among the 243 patients who received either the 2-step up or 3-step up dosage schedule was the following: Any grade CRS 35%; Grade 1 CRS: 28%; Grade 2 CRS: 7%. 0 0.8 0 (N=243) (N=238) Skin and subcutaneous tissue disorders Rash Rash includes blister, dermatitis, erythema, rash, skin exfoliation, skin reaction, toxic skin eruption, urticaria and related terms. 46 11 Only Grade 3 adverse reactions occurred. 34 6 Infections and infestations Upper respiratory tract infections Upper respiratory tract infections include sinusitis, laryngitis, nasopharyngitis, pharyngitis, rhinitis, rhinovirus infection, upper respiratory tract infection, and related terms. 33 3.3 18 0.4 Pneumonia Pneumonia includes pneumonia, COVID-19 pneumonia, pneumonia fungal, Pneumocystis jirovecii pneumonia, pneumonia cytomegaloviral, and related terms. 24 16 8 Includes one case with a fatal outcome. 4.6 COVID-19 COVID-19 includes COVID-19, COVID-19 pneumonia, coronavirus infection, coronavirus pneumonia. 23 5 13 1.3 General disorders and administration site conditions Fatigue Fatigue includes asthenia, fatigue, lethargy, malaise. 31 4.9 24 2.1 Injection site reactions 27 0 0.4 0 Fever 23 0.4 11 1.3 Gastrointestinal disorders Constipation 26 0.8 21 0 Mucositis Mucositis includes gingival pain, glossitis, mouth ulceration, mucosal infection, mucosal inflammation, oral discomfort, oral mucosal exfoliation, oropharyngeal pain, stomatitis. 12 0 3.4 0 Nervous system disorders Neurological changes Neurological changes include brain fog, cognitive disorder, confusional state, disturbance in attention, dysphonia, epilepsy, essential tremor, gait disturbance, hypoacusis, lethargy, loss of consciousness, memory impairment, somnolence, syncope, tremor, vertigo, and ICANS. 15 1.2 8 1.3 Headache 11 0 3.8 0 Psychiatric disorders Insomnia 14 0 2.9 0 Other clinically relevant adverse reactions include: Gastrointestinal disorders: diarrhea (26%), nausea (16%), abdominal pain (11%), vomiting (4.1%) Musculoskeletal and connective tissue disorders: musculoskeletal pain (14%), arthralgia (8%) Nervous system disorders: peripheral neuropathy (12%), dizziness (7%), ICANS (0.8%) General disorders: edema (12%) Infections: cytomegalovirus infection (7%), herpesvirus infection (7%), sepsis (2.9%) Blood and lymphatic system disorders: febrile neutropenia (6%) Neoplasms: tumor flare (1.2%) Table 14 summarizes laboratory abnormalities in EPCORE FL-1. Grade 4 laboratory abnormalities in ≥ 2% of the EPKINLY arm included decreases in neutrophils (41%), lymphocytes (13%), and platelets decreased (4.1%). Table 14: Select Laboratory Abnormalities (≥ 30% All Grade and ≥ 10% Higher) That Worsened from Baseline in Patients with Relapsed or Refractory FL Who Received EPKINLY in Combination with Lenalidomide and Rituximab in EPCORE FL-1 Laboratory Abnormality EPKINLY + Lenalidomide and Rituximab The denominator used to calculate the rate varied from 240 to 242 in the EPKINLY arm, and 225 to 236 in the comparator arm, based on the number of patients with a baseline value and at least one post-treatment value. Lenalidomide and Rituximab All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Laboratory abnormalities were graded based on CTCAE Version 5.0 Hematology Neutrophils decreased 86 67 75 41 Lymphocytes decreased 86 62 56 15 Hemoglobin decreased 66 7 52 4.7 Platelets decreased 50 10 37 7 Chemistry Alanine aminotransferase increased 58 7 36 0.9 Phosphate decreased CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value < Lower Limit of Normal (LLN). 49 N/A 28 N/A Sodium decreased 43 4.1 23 2.6 Potassium decreased 41 9 20 4.7 Aspartate aminotransferase increased 40 2.9 29 0.9 EPCORE NHL-1 The safety of EPKINLY as monotherapy was evaluated in EPCORE NHL-1, a single-arm study of patients with relapsed or refractory FL after two or more lines of systemic therapy who received EPKINLY following a 2-step up dosage schedule (N=127) [see Clinical Studies (14.2) ] . A separate dose optimization cohort evaluated the recommended 3-step up dosage schedule for CRS mitigation (N=86), where EPKINLY was administered via subcutaneous injection until disease 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, 3 mg on Day 15, and 48 mg on Day 22 Cycle 2-3: EPKINLY 48 mg on Days 1, 8, 15, and 22 Cycles 4-9: EPKINLY 48 mg on Days 1 and 15 Cycles 10 and beyond: EPKINLY 48 mg on Day 1 With the exception of CRS, the safety results presented below and in Tables 15 and 16 represent data from patients who received the 2-step up dosage schedule. The data presented for CRS reflects the 86 patients who received the recommended 3-step up dosage schedule. The study excluded patients with CNS involvement of lymphoma, allogeneic HSCT or solid organ transplant, ongoing active infection, any patients with known impaired T-cell immunity, creatinine clearance < 45 ml/min, alanine aminotransferase > 3 times the upper limit of normal, and a cardiac ejection fraction < 45%. Recommended 3-step up Dosage Schedule Of the 86 patients with relapsed or refractory FL who received EPKINLY following the recommended 3-step up dosage schedule, the median age was 63 years (range: 33 to 90), 57% were male, and 100% had an ECOG performance status of 0 or 1. The median duration of exposure was 5 cycles (range: 1 to 12 cycles). CRS occurred in 49% of patients, with Grade 1 CRS occurring in 45% and Grade 2 in 9% of patients. Serious adverse reactions due to CRS occurred in 28% of patients who received EPKINLY. Dose interruptions due to CRS occurred in 19% of patients who received EPKINLY. 2-step up Dosage Schedule Of the 127 patients with relapsed or refractory FL who received EPKINLY following a 2-step up dosage schedule, the median age was 65 years (range: 39 to 84), 62% were male, and 95% had an ECOG performance status of 0 or 1 [see Clinical Studies (14.2) ] . The median duration of exposure for patients receiving EPKINLY was 8 cycles (range: 1 to 33 cycles). Serious adverse reactions occurred in 66% of patients who received EPKINLY. Serious adverse reactions in ≥ 5% of patients included CRS, COVID-19, pneumonia, and second primary malignancies. Fatal adverse reactions occurred in 9% of patients who received EPKINLY, including COVID-19 (5%), pneumonitis (1.6%), cardiac failure (0.8%), pneumonia (0.8%), and sepsis (0.8%). Permanent discontinuation of EPKINLY due to an adverse reaction occurred in 19% of patients who received EPKINLY. Adverse reactions which resulted in permanent discontinuation of EPKINLY in ≥ 2% of patients included COVID-19, Hepatitis E, pneumonitis, and second primary malignancy. Dosage interruptions of EPKINLY due to an adverse reaction occurred in 59% of patients who received EPKINLY. Adverse reactions which required dosage interruption in ≥ 5% of patients included COVID-19, CRS, pneumonia, upper respiratory tract infection, and fatigue. The most common (≥ 20%) adverse reactions were injection site reactions, CRS, COVID-19, fatigue, upper respiratory tract infection, musculoskeletal pain, rash, diarrhea, pyrexia, cough, and headache. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and decreased hemoglobin. Table 15 summarizes the adverse reactions in EPCORE NHL-1. Table 15: Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory FL Who Received EPKINLY as Monotherapy in EPCORE NHL-1 Adverse Reaction Adverse reactions were graded based on CTCAE Version 5.0. EPKINLY All Grades (%) Grade 3 or 4 (%) (N=86) The frequency of CRS is based on 86 patients with FL who received the recommended 3-step up dosage schedule in EPCORE NHL-1 [see Dosage and Administration (2.2) ] . Immune system disorders Cytokine release syndrome CRS was graded using ASTCT consensus criteria (Lee et al., 2019). The frequency of CRS based on the 127 patients with FL who received the 2-step up dosage schedule in EPCORE NHL-1 was the following: Any grade CRS 66%; Grade 1 CRS: 50%; Grade 2 CRS: 26%; Grade 3 CRS: 1.6%. 49 0 (N=127) General disorders and administration site conditions Injection site reactions Includes related grouped terms. 58 0 Fatigue 37 5 Only Grade 3 adverse reactions occurred. Pyrexia 26 2 Edema 17 0 Infections and Infestations COVID-19 COVID-19 includes COVID-19, COVID-19 pneumonia, SARS-CoV-2 test positive. 40 19 Upper respiratory tract infection Upper respiratory tract infection includes preferred terms with upper respiratory infection and sinusitis, laryngitis viral, nasopharyngitis, oropharyngitis fungal, pharyngitis, rhinitis, rhinovirus infection, tonsillitis. 29 2 Pneumonia Pneumonia includes preferred terms with pneumonia, bronchopulmonary aspergillosis, infectious pleural effusion, infective exacerbation of bronchiectasis, Pneumocystis jirovecii pneumonia, pneumonia respiratory syncytial viral. 17 13 Urinary tract infection 13 5 Herpesvirus infection Herpesvirus infection includes herpes simplex, herpes simplex reactivation, herpes virus infection, herpes zoster, oral herpes, varicella zoster virus infection. 12 1.6 Musculoskeletal and connective tissue disorders Musculoskeletal pain 28 0.8 Arthralgia 14 0.8 Skin and subcutaneous disorders Rash 28 0 Gastrointestinal disorders Diarrhea 26 1.6 Nausea 17 0 Abdominal pain 17 0.8 Constipation 16 0 Mucositis Mucositis includes aphthous ulcer, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, stomatitis, tongue ulceration. 12 0 Respiratory disorders Cough 20 0 Dyspnea 17 0 Nervous system disorders Headache 20 0 Neurological changes Neurological changes includes amnesia, aphasia, balance disorder, brain fog, confusional state, dysphonia, encephalopathy, extrapyramidal disorder, hallucination, hypoacusis, memory impairment, mental status changes, tremor, vertigo. 13 0 Peripheral neuropathy and paresthesia Peripheral neuropathy and paresthesia includes bell's palsy, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy. 13 1.6 Dizziness 11 0 Psychiatric disorders Insomnia 13 0 Renal and urinary disorders Renal insufficiency Renal insufficiency includes acute kidney injury, blood creatinine increased, renal impairment. 10 1.6 Clinically relevant adverse reactions in < 10% of patients (N=127) who received EPKINLY included vomiting, pruritus, hepatotoxicity, ICANS, lower respiratory tract infections, cardiac arrhythmias, respiratory tract infections, pneumonitis, second primary malignancy, vision changes, cellulitis, febrile neutropenia, cardiac failure, cytomegalovirus infection and sepsis. Table 16 summarizes laboratory abnormalities in EPCORE NHL-1. Table 16: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory FL Who Received EPKINLY in EPCORE NHL-1 Laboratory Abnormality Laboratory abnormalities were graded based on CTCAE Version 5.0 EPKINLY The denominator used to calculate the rate varied from 123 to 127 based on the number of patients with a baseline value and at least one post-treatment value. (N=127) All Grades Grade 3 or 4 (%) Hematology Lymphocytes decreased 94 82 Hemoglobin decreased 59 10 White blood cells decreased 58 19 Neutrophils decreased 55 30 Platelets decreased 49 8 Chemistry Sodium decreased 51 1.6 ALT increased 47 8 AST increased 44 6 Creatinine increased 36 0.8 Alkaline phosphatase increased 29 0 Bilirubin increased 28 1.6 Potassium decreased 20 3.1 Magnesium decreased 20 0.8 6.2 Postmarketing Experience The following adverse reaction has been identified during post-approval use of EPKINLY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders : Hemophagocytic Lymphohistiocytosis (HLH)

8.1 Pregnancy Risk Summary Based on the mechanism of action, EPKINLY may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of EPKINLY in pregnant women to evaluate for a drug-associated risk. No animal reproductive or developmental toxicity studies have been conducted with epcoritamab-bysp. Epcoritamab-bysp causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD20 on B-cells and the finding of B-cell depletion in non-pregnant animals, epcoritamab-bysp can cause B-cell lymphocytopenia in infants exposed to epcoritamab-bysp in-utero. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, EPKINLY has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.