Epcoritamab-bysp (Monograph)

Brand name: Epkinly
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jan 10, 2025. Written by ASHP.

Warning

Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving epcoritamab-bysp.
Initiate treatment with the epcoritamab-bysp step-up dosage schedule to reduce the incidence and severity of CRS.
Withhold epcoritamab-bysp until CRS resolves or permanently discontinue based on severity.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), including life-threatening and fatal reactions, can occur with epcoritamab-bysp.
Monitor patients for neurological signs or symptoms of ICANS during treatment.
Withhold epcoritamab-bysp until ICANS resolves or permanently discontinue based on severity.

Introduction

Bispecific CD20-directed CD3 T-cell engager; antineoplastic agent.

Uses for Epcoritamab-bysp

Diffuse Large B-cell Lymphoma and High-grade B-cell Lymphoma

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.

Approved under accelerated approval based on response rate and durability of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Follicular Lymphoma

Treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy; designated an orphan drug by FDA for this use.

Epcoritamab-bysp Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor CBC throughout treatment.
Monitor all patients for cytokine release syndrome.
Monitor all patients for immune effector cell-associated neurotoxicity syndrome.
Monitor patients for signs and symptoms of infection prior to and during treatment and treat appropriately. Avoid administration in patients with active infections.
Patients with diffuse large B-cell lymphoma or high-grade B-cell lymphoma should be hospitalized for 24 hours following administration of first full 48 mg dose.

Premedication and Prophylaxis

Provide Pneumocystis jirovecii pneumonia (PJP) prophylaxis prior to starting treatment.
Consider initiating prophylaxis against herpes virus to prevent herpes zoster reactivation.
Administer pre- and post-administration medications outlined in Table 1 to reduce risk of cytokine release syndrome.

Dexamethasone is preferred corticosteroid when available.

Permanently discontinue after Grade 4 cytokine release syndrome.

Table 1. Recommended Pre- and Post-Medications1
Cycle	Patients Requiring Medication	Medication	Administration Recommendation
Cycle 1	All patients	Dexamethasone 15 mg (oral or IV) or prednisolone 100 mg (oral or IV) or equivalent	30—120 minutes prior to each weekly administration and for 3 consecutive days following each weekly administration in Cycle 1
Cycle 1	All patients	Diphenhydramine 50 mg (oral or IV) or equivalent	30—120 minutes prior to each weekly administration
Cycle 1	All patients	Acetaminophen 650—1,000 mg orally	30—120 minutes prior to each weekly administration
Cycle 2+	Patients who experienced Grade 2 or 3 cytokine release syndrome with previous dose	Dexamethasone 15 mg (oral or IV) or prednisolone 100 mg (oral or IV) or equivalent	30—120 minutes prior to next administration after a Grade 2 or 3 cytokine release syndrome event and for 3 consecutive days following next administration until epcoritamab-bysp is given without subsequent cytokine release syndrome of Grade 2 or higher

Dispensing and Administration Precautions

Certain doses require dilution. Improper preparation may lead to improper dosage. Consult manufacturer's labeling for detailed instructions.

Other General Considerations

Administer to well-hydrated patients.

Administration

For sub-Q injection only by a healthcare professional with appropriate medical support to manage severe reactions such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.

Administer in 28-day cycles until disease progression or unacceptable toxicity.

Doses of 0.16 mg and 0.8 mg require dilution prior to administration. Dosages of 3 mg and 48 mg do not require dilution.

Vial should be swirled gently prior to withdrawal of dose; do not invert, vortex, or vigorously shake.

Vials containing unused drug should be discarded.

To minimize injection pain, allow to equilibrate to room temperature for no more than 1 hour prior to administration.

Inspect product for particulate matter and discoloration prior to administration, whenever solution and container permit; should be clear to slightly opalescent, colorless to slightly yellow solution, free of visible particles.

Inject required volume into sub-Q tissue of lower part of abdomen (preferred location) or thigh. Do not inject into tattoos or scars or areas where skin is red, bruised, tender, hard, or not intact.

Changing injection site from left or right side (or vice versa) is recommended, especially during weekly administrations (Cycles 1 to 3).

Dilution: Empty Sterile Vial Method

Two Dilution Method (0.16 mg Dose Preparation)

Retrieve 4 mg/0.8 mL vial from refrigerator and allow to come to room temperature for no more than 1 hour. Gently swirl; do not invert, vortex, or vigorously shake.

Using aseptic technique, perform first dilution. Label appropriately sized empty vial as “Dilution A.” Transfer 0.8 mL of epcoritamab-bysp into Dilution A vial. Transfer 4.2 mL of 0.9% sodium chloride injection into Dilution A vial. Gently swirl Dilution A vial for 30 to 45 seconds. Initial diluted solution contains epcoritamab-bysp 0.8 mg/mL.

Using aseptic technique, perform second dilution. Label an appropriately sized empty vial as “Dilution B.” Transfer 2 mL of solution from Dilution A vial into Dilution B vial. Dilution A vial is no longer needed. Transfer 8 mL of 0.9% sodium chloride injection into Dilution B vial to make final concentration of 0.16 mg/mL. Gently swirl Dilution B vial for 30 to 45 seconds.

Withdraw 1 mL of diluted epcoritamab-bysp from Dilution B vial into a syringe. Label syringe with the dose strength (0.16 mg) and time of day. Discard vial containing the unused drug.

One Dilution Method (0.8 mg Dose Preparation)

Retrieve 4 mg/0.8 mL vial from refrigerator and allow to come to room temperature for no more than 1 hour. Gently swirl vial; do not invert, vortex, or vigorously shake.

Using aseptic technique, label appropriately sized empty vial as “Dilution A.” Transfer 0.8 mL of epcoritamab-bysp into Dilution A vial. Transfer 4.2 mL of 0.9% sodium chloride injection into Dilution A vial. Gently swirl Dilution A vial for 30 to 45 seconds. Diluted solution contains epcoritamab-bysp 0.8 mg/mL.

Withdraw 1 mL of diluted epcoritamab-bysp solution from Dilution A vial into a syringe. Label syringe with dose strength (0.8 mg) and time of day. Discard vial containing unused drug.

Dilution: Sterile Syringe Method

Two Dilution Method (0.16 mg Dose Preparation)

Retrieve 4 mg/0.8 mL vial from refrigerator and allow to come to room temperature for no more than 1 hour. Gently swirl vial; do not invert, vortex, or vigorously shake.

Using aseptic technique, perform first dilution. Label appropriately sized syringe as “Dilution A." Withdraw 4.2 mL of 0.9% sodium chloride injection into Dilution A syringe. Include approximately 0.2 mL air in syringe. In new syringe labeled “Syringe 1,” withdraw 0.8 mL of epcoritamab-bysp. Connect two syringes and push 0.8 mL of epcoritamab-bysp into Dilution A syringe. Initially diluted solution contains 0.8 mg/mL of epcoritamab-bysp. Gently mix by inverting connected syringes 180 degrees 5 times. Disconnect syringes and discard Syringe 1.

Using aseptic technique, perform second dilution. Label appropriately sized syringe as “Dilution B.” Withdraw 8 mL of 0.9% sodium chloride injection into Dilution B syringe. Include approximately 0.2 mL air in syringe. Label another appropriately sized syringe as “Syringe 2.” Connect Syringe 2 to Dilution A syringe and transfer 2 mL of solution Syringe 2. Dilution A syringe is no longer needed.

Connect Syringe 2 to Dilution B syringe and push 2 mL of solution into Dilution B syringe to make a final concentration of 0.16 mg/mL. Gently mix by inverting connected syringes 180 degrees 5 times. Disconnect syringes and discard Syringe 2.

Connect and transfer 1 mL of diluted epcoritamab-bysp from Dilution B syringe into new syringe. Dilution B syringe is no longer needed. Label syringe with dose strength (0.16 mg) and time of day. Discard vial containing unused drug.

One Dilution Method (0.8 mg Dose Preparation)

Retrieve 4 mg/0.8 mL vial from refrigerator and allow to come to room temperature for no more than 1 hour. Gently swirl vial; do not invert, vortex, or vigorously shake.

Using aseptic technique, perform first dilution. Label appropriately sized syringe as “Dilution A.” Withdraw 4.2 mL of 0.9% sodium chloride injection into Dilution A syringe. Include approximately 0.2 mL air in syringe. In new syringe labeled as “Syringe 1,” withdraw 0.8 mL of epcoritamab-bysp. Connect two syringes and push 0.8 mL of epcoritamab-bysp into Dilution A syringe to make final concentration of 0.8 mg/mL. Gently mix by inverting connected syringes 180 degrees 5 times. Disconnect syringes and discard Syringe 1.

Connect new syringe to the Dilution A syringe and transfer 1 mL of diluted epcoritamab-bysp into new syringe. Dilution A syringe is no longer needed. Label syringe with dose strength (0.8 mg) and time of day. Discard vial containing unused drug.

Dosage

Adults

Diffuse Large B-cell Lymphoma or High-grade B-cell Lymphoma

Sub-Q

Administer in 28-day cycles until disease progression or unacceptable toxicity according to recommendations in Tables 2 and 3.

Table 2. 2-step Up Dosage Schedule for Diffuse Large B-cell or High-grade B-Cell Lymphoma: Cycle 11
Day of Treatment	Dose Step	Dosage
1	Step-up Dose 1	0.16 mg
8	Step-up Dose 2	0.8 mg
15	First Full Dose	48 mg
22	Full Dose	48 mg

Each cycle = 28 days

Table 3. Dosage Schedule for Diffuse Large B-cell or High-grade B-Cell Lymphoma: Cycles 2 and Beyond1
Cycle of Treatment	Day of Treatment	Dosage
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

Follicular Lymphoma

Administer in 28-day cycles until disease progression or unacceptable toxicity according to recommendations in Tables 4 and 5.

Table 4. 3-step Up Dosage Schedule for Follicular Lymphoma: Cycle 1
Day of Treatment	Dose Step	Dosage
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

Each cycle = 28 days

Table 5. Dosage Schedule for Follicular Lymphoma: Cycle 2 and Beyond1
Cycle of Treatment	Day of Treatment	Dosage
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

Therapy Interruptions

If dose is delayed, restart therapy based on recommendations in Table 6 for diffuse large B-cell or high-grade B-cell lymphoma or Table 7 for follicular lymphoma.

Administer pretreatment medication prior to epcoritamab-bysp dose and monitor accordingly.

Table 6. Recommendations for Restarting Epcoritamab-bysp for Diffuse Large B-cell Lymphoma or High-Grade B Cell Lymphoma after Dosage Delay1
Last Dose Administered	Time Since the Last Dose was Administered	Action for Next Dose(s)
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 repeat of Cycle 1 schedule, resume planned treatment schedule.
0.8 mg (e.g., on Cycle 1 Day 8)	14 days or less	Administer 48 mg, then resume planned treatment schedule.
0.8 mg (e.g., on Cycle 1 Day 8)	More than 14 days	Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following repeat of Cycle 1 schedule, resume planned treatment schedule.
48 mg (e.g., on Cycle 1 Day 15 onwards)	6 weeks or less	Administer 48 mg, then resume planned treatment schedule.
48 mg (e.g., on Cycle 1 Day 15 onwards)	More than 6 weeks	Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following repeat of Cycle 1 schedule, resume planned treatment schedule.

Administer pretreatment medication prior to epcoritamab-bysp dose and monitor patients accordingly.

Table 7. Recommendations for Restarting Epcoritamab-bysp for Follicular Lymphoma After Dosage Delay1
Last Dose Administered	Time Since Last Dose was Administered	Action for Next Dose(s)
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 repeat of Cycle 1 schedule, resume 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 repeat of Cycle 1 schedule, resume planned treatment schedule.
3 mg (e.g., on Cycle 1 Day 15)	14 days or less	Administer 48 mg, then resume planned treatment schedule.
3 mg (e.g., on Cycle 1 Day 15)	More than 14 days	Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following repeat of Cycle 1 schedule, resume planned treatment schedule.
48 mg (e.g., on Cycle 1 Day 22 onwards)	6 weeks or less	Administer 48 mg, then resume planned treatment schedule.
48 mg (e.g., on Cycle 1 Day 22 onwards)	More than 6 weeks	Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following repeat of Cycle 1 schedule, resume planned treatment schedule.

Dosage Modifications for Toxicity

If cytokine release syndrome (CRS) suspected, withhold epcoritamab-bysp until resolved. Manage according to recommendations in Table 8 and consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS.

At first signs of immune effector cell-associated neurological toxicity syndrome (ICANS), withhold epcoritamab-bysp and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care. Manage ICANS according to recommendations in Table 9 and consider further management per current practice guidelines.

Manage adverse reactions other than CRS and ICANS according to recommendations in Table 10.

Based on the American Society for Transplantation and Cellular Therapy 2019 grading for CRS.

Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow these management guidelines.

Low-flow oxygen defined as oxygen delivered at <6 L/minute; high-flow oxygen defined as oxygen delivered at ≥6 L/minute.

Refer to Table 6 or 7 for information on restarting after dosage delays.

If Grade 2 or 3 CRS occurs with the second full dose (48 mg) or beyond, administer pre- and post-administration medications with each subsequent dose until an epcoritamab-bysp dose is given without subsequent CRS Grade 2 or higher. Refer to Table 1 for additional information on pre- and post-administration medications.

Table 8. Recommendations for Management of Cytokine Release Syndrome1
Grade	Presenting Symptoms	Recommended Actions
Grade 1	Temperature ≥38°C^b	Withhold epcoritamab-bysp and manage per current practice guidelines. Ensure CRS symptoms resolved prior to next dose.
Grade 2	Temperature ≥38°C with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen by nasal cannula or blow-by.	Withhold epcoritamab-bysp and manage per current practice guidelines. Ensure CRS symptoms resolved prior to the next dose. Administer premedication prior to next dose. For next dose, monitor more frequently and consider hospitalization.
Grade 3	Temperature ≥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 epcoritamab-bysp and manage per current practice guidelines, which may include intensive care. Ensure CRS symptoms resolved prior to next dose. Administer premedication prior to next dose. Hospitalize for next dose.
Grade 3	Recurrent Grade 3 CRS	Permanently discontinue epcoritamab-bysp. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care.
Grade 4	Temperature ≥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 epcoritamab-bysp. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care.

Based on American Society for Transplantation and Cellular Therapy 2019 grading for ICANS.

Management is determined by most severe event not attributable to any other cause.

If patient is arousable and able to perform 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 10 = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.

Not attributable to any other cause.

See Table 6 and Table 7 for recommendations on restarting epcoritamab-bysp after dosage delays.

All references to dexamethasone administration are dexamethasone or equivalent.

Table 9. Recommendations for Management of Immune Effector Cell-Associated Neurotoxicity Syndrome1
Grade	Presenting Symptoms	Recommended Actions
Grade 1	Immune Effector Cell-associated Encephalopathy (ICE) score 7—9, or depressed level of consciousness: awakens spontaneously	Withhold epcoritamab-bysp until ICANS resolves. Monitor neurological symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medications for seizure prophylaxis.
Grade 2	ICE score 3—6, or depressed level of consciousness: awakens to voice	Withhold epcoritamab-bysp until ICANS resolves. Administer dexamethasone 10 mg IV 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 medications for seizure prophylaxis.
Grade 3	ICE score 0—2, or depressed level of consciousness: awakens only to tactile stimuli, Or seizures, either: any clinical seizure, focal or generalized, that resolves rapidly, or non-convulsive seizures on electroencephalogram that resolve with intervention, Or raised intracranial pressure: focal/local edema on neuroimaging.	First occurrence of Grade 3 ICANS: withhold epcoritamab-bysp until ICANS resolves. Administer dexamethasone 10 mg IV 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 medications for seizure prophylaxis. Provide supportive therapy, which may include intensive care.
Grade 3	Recurrent Grade 3 ICANS	Permanently discontinue epcoritamab-bysp. Administer dexamethasone 10 mg IV every 6 hours. Continue dexamethasone use until resolution to ≤Grade 1, 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 medications for seizure prophylaxis. Provide supportive therapy, which may include intensive care.
Grade 4	ICE score of 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 epcoritamab-bysp. Administer dexamethasone 10 mg IV every 6 hours. Continue dexamethasone until resolution to Grade 1 or less, then taper. Alternatively, consider administration of methylprednisolone 1,000 mg IV per day and continue methylprednisolone 1,000 mg IV per day for 2 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 medications for seizure prophylaxis. Provide supportive therapy, which may include intensive care.

Based on National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0.

See Table 6 or Table 7 for recommendations on restarting epcoritamab-bysp after dosage delays.

Table 10. Recommended Dosage Modification for Other Adverse Reactions1
Adverse Reaction	Severity	Recommended Action
Infections	Grade 1—4	Withhold in active infection until infection resolves. For Grade 4, consider permanent discontinuation.
Neutropenia	Absolute neutrophil count less than 500 cells/mm³	Withhold until absolute neutrophil count is 500 cells/mm³ or higher.
Thrombocytopenia	Platelet count less than 50,000 cells/mm³	Withhold until platelet count is 50,000 cells/mm³ or higher.
Other Adverse Reactions	Grade 3 or higher	Withhold until the toxicity resolves to Grade 1 or baseline.

Special Populations

Hepatic Impairment

No specific population dosage recommendations at this time.

Renal Impairment

No specific population dosage recommendations at this time.

Geriatric Patients

No specific population dosage recommendations at this time.

Cautions for Epcoritamab-bysp

Contraindications

None.

Warnings/Precautions

Warnings

Cytokine Release Syndrome

Epcoritamab-bysp can cause CRS, including serious or life-threatening reactions (see Boxed Warning).

Patients with diffuse large B-cell lymphoma or high-grade B-cell lymphoma should be hospitalized for 24 hours following administration of first full 48 mg dose.

Signs and symptoms of CRS include pyrexia, hypotension, hypoxia, dyspnea, chills, and tachycardia. Concurrent neurological adverse reactions observed in patients with large B-cell lymphoma included headache, confusional state, tremors, dizziness, and ataxia. Concurrent neurological adverse reactions observed in patients with follicular lymphoma included headache and dizziness.

Initiate therapy according to step-up dosage schedule. Administer pretreatment medications to reduce risk of CRS and monitor for potential CRS accordingly.

At 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 epcoritamab-bysp based on severity of CRS.

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.

Immune Effector Cell-associated Neurotoxicity Syndrome

Epcoritamab-bysp can cause life-threatening and fatal ICANS (see Boxed Warning).

Clinical manifestations include, but are not limited to, confusional state, lethargy, tremor, dysphagia, aphasia, and non-convulsive status epilepticus. Onset can be concurrent with CRS, following resolution of CRS, or in absence of CRS.

Monitor for potential ICANS. At the first signs or symptoms of ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or discontinue epcoritamab-bysp per recommendations and consider further management per current practice guidelines.

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.

Other Warnings/Precautions

Infections

Can cause serious and fatal infections.

Monitor for signs and symptoms of infection prior to and during treatment and treat appropriately. Avoid administration in patients with active infections. Provide prophylaxis against Pneumocystis jirovecii pneumonia (PJP) prior to initiating treatment; consider initiating prophylaxis against herpes virus.

Withhold or consider permanent discontinuation of epcoritamab-bysp based on infection severity.

Cytopenias

Can cause serious or severe cytopenias, including neutropenia, anemia, and thrombocytopenia.

Monitor CBC throughout treatment. Based on severity of cytopenias, temporarily withhold or permanently discontinue. Consider prophylactic granulocyte colony-stimulating factor administration as applicable.

Embryo-fetal Toxicity

Based on mechanism of action, may cause fetal harm when administered to pregnant women. Advise pregnant women of potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment and for 4 months after last dose.

Immunogenicity

Anti-epcoritamab-bysp antibodies developed in 2.6% (4/156) of patients with large B-cell lymphoma and 4.2% of patients with follicular lymphoma in the EPCORE NHL-1 study (up to 10 cycles). Because of low occurrence of ADA, effects of antibodies on pharmacokinetics, pharmacodynamics, safety, and effectiveness are unknown.

Specific Populations

Pregnancy

Based on mechanism of action, may cause fetal harm when administered to pregnant women. No available data on use in pregnant women to evaluate drug-associated risk. No animal productive or development toxicity studies have been conducted.

Epcoritamab-bysp causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance.

Human immunoglobulin G (IgG) is known to cross placenta; therefore, has potential to be transmitted from mother to developing fetus.

Advise women of potential risk to fetus.

Lactation

No data on presence in human milk, effects on breast-fed child, or effects on milk production. Because maternal IgG is present in human milk, and there is potential for epcoritamab-bysp absorption leading to serious adverse reactions in a breast-fed child, advise women not to breastfeed during treatment and for 4 months after last dose.

Females and Males of Reproductive Potential

May cause fetal harm when administered to a pregnant woman.

Verify pregnancy status in females of reproductive potential prior to initiation. Advise females of reproductive potential to use effective contraception during treatment and for 4 months after last dose.

Pediatric Use

Safety and effectiveness not established.

Geriatric Use

No clinically meaningful differences in safety or efficacy observed between patients with relapsed or refractory large B-cell lymphoma who were ≥65 years of age compared with younger adult patients.

In patients with relapsed or refractory follicular lymphoma, there was a higher rate of adverse reactions, primarily infections, including COVID-19, in patients older than 65 years of age compared to younger adult patients. No overall difference in efficacy observed in patients with relapsed or refractory follicular lymphoma who were ≥65 years of age compared with younger adult patients.

Common Adverse Effects

Most common adverse effects (≥20%) in large B-cell lymphoma: cytokine release syndrome, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, diarrhea. Most common Grade 3 to 4 laboratory abnormalities (≥10%): decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, decreased platelets.

Most common adverse effects (≥20%) in follicular lymphoma: injection site reactions, cytokine release syndrome, COVID-19, fatigue, upper respiratory tract infection, musculoskeletal pain, rash, diarrhea, pyrexia, cough, headache. Most common Grade 3 to 4 laboratory abnormalities (≥10%): decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin.

Drug Interactions

Expected to be metabolized into small peptides by catabolic pathways. No clinical studies evaluating drug interaction potential have been conducted.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Epcoritamab-bysp causes release of cytokines that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates. Increased exposure of CYP substrates more likely to occur after first dose of epcoritamab-bysp and up to 14 days after first 48 mg dose, and during and after cytokine release syndrome. For certain CYP substrates, minimal changes in concentration may lead to serious adverse reactions. Monitor for toxicity or drug concentrations of such CYP substrates when co-administered with epcoritamab-bysp.

Epcoritamab-bysp Pharmacokinetics

Absorption

Bioavailability

AUC increases more than proportionally over dose range from 1.5 to 60 mg.

Onset

Circulating B-cells decrease to undetectable levels (<10 cells/microliter) after administration of approved recommended dose in patients who had detectable B-cells at treatment initiation by Cycle 1 Day 15; depletion was sustained while patients remained on treatment.

C_max achieved after the first dose of Cycle 4.

T_max after first full dose and end of Cycle 3: 4 (range: 0.3—7) days and 2.3 (0.3—3.2 days), respectively.

Special Populations

In patients who received recommended dosage, geometric mean average concentration following first full 48 mg dose was 31% lower in higher body weight group (85 to 172 kg) and 13% higher in lower body weight group (39 to 65 kg) compared to patients with body weight of 65 to <85 kg.

Distribution

Extent

May be present in breast milk.

Elimination

Metabolism

Expected to be metabolized into small peptides by catabolic pathways.

Half-life

Approximately 22 days (58%) at end of Cycle 3.

Special Populations

No clinically significant differences observed between patients with relapsed or refractory large B-cell lymphoma and patients with relapsed or refractory follicular lymphoma.

No clinically significant differences observed based on age (range: 20 to 89 years), sex, race, mild to moderate renal impairment (Cl_cr30 to <90 mL/minute as estimated by Cockcroft-Gault formula), and mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin 1—1.5 times ULN and any AST level) accounting for differences in body weight.

The effects of severe renal impairment (Cl_cr 15 to <30 mL/minute), end-stage renal disease (Cl_cr <15 mL/minute), or moderate to severe hepatic impairment (total bilirubin >1.5 times ULN and any AST level) on pharmacokinetics are unknown.

Stability

Storage

Sub-Q injection

Store refrigerated at 2-8°C. Keep in original carton to protect from light. Do not freeze. Do not shake.

If prepared syringe not used immediately, store solution refrigerated at 2-8°C for up to 24 hours or at room temperature at 20-25°C for up to 12 hours. Total storage time from start of dose preparation to administration should not exceed 24 hours. Protect from direct sunlight. Discard unused solution beyond allowable storage time.

Actions

Bispecific CD20-directed CD3 T-cell engager; humanized bispecific IgG antibody.
T-cell specific antibody that binds to CD3 receptor expressed on surface of T-cells and CD20 expressed on surface of lymphoma cells and healthy B-lineage cells.
In vitro, activated T-cells, caused the release of proinflammatory cytokines, and induced lysis of B-cells.
Transient elevation of circulating cytokines (interleukin [IL]-2, IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma) observed at doses of 0.04 mg and above. After administration of approved recommended dosages, cytokine levels increased within 24 hours after first dose on Cycle 1 Day 1, generally reached maximum levels after first 48 mg dose, and returned to baseline prior to second 48 mg full dose.
Manufactured in Chinese hamster ovary cells using recombinant DNA technology.

Advice to Patients

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).
Inform patients of the risk of CRS and to immediately contact their clinician should signs and symptoms associated with CRS (e.g., pyrexia, hypotension, hypoxia, chills, tachycardia, headache, and dyspnea) occur at any time. Advise patients with diffuse B-cell lymphoma or high-grade B-cell lymphoma that they should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg. Advise all patients who experience symptoms that impair consciousness not to drive and to refrain from operating heavy or potentially dangerous machinery until events resolve.
Advise patients of the risk of ICANS to immediately contact their clinician for signs and symptoms associated with ICANS, which may manifest, for example, as confusional state, lethargy, tremor, dysgraphia, aphasia, and non-convulsive status epilepticus, and that the onset of events may be delayed. Advise patients who experience symptoms of ICANS that impair consciousness to refrain from driving or operating heavy or potentially dangerous machinery until symptoms of ICANS resolve.
Advise patients on the risks of serious infections and to contact their clinician for signs or symptoms of serious infection. Inform patients that prophylaxis against certain infections, such as Pneumocystis jiroveciipneumonia and herpes virus, may be needed.
Inform patients on the signs and symptoms of cytopenias, including neutropenia and febrile neutropenia, anemia, and thrombocytopenia.
Advise pregnant women of the potential risk to the fetus. Inform females of reproductive potential that their clinician will verify pregnancy status prior to initiating epcoritamab-bysp. Advise females of reproductive potential to inform their clinician if they are pregnant or plan to become pregnant.
Advise females of reproductive potential to use effective contraception during treatment with epcoritamab-bysp and for 4 months after the last dose.
Advise patients not to breastfeed during treatment with epcoritamab-bysp and for 4 months after the last dose.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Epcoritamab-bysp is obtained through designated specialty pharmacies and distributors. Contact manufacturer or consult the epcoritamab-bysp website ([Web]) for specific availability information.