This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
EPKINLY safely and effectively. See full prescribing information for
EPKINLY.
EPKINLY™ (epcoritamab-bysp) injection, for subcutaneous use
Initial U.S. Approval: 2023

• Patients should be hospitalized for 24 hours after administration of the
Cycle 1 Day 15 dosage of 48 mg. (2.1)• Administer premedications and prophylaxis as recommended. (2.4, 2.5)
• Dosages of EPKINLY 0.16 mg and 0.8 mg require dilution prior toadministration. (2.7)• See Full Prescribing Information for instructions on preparation andadministration. (2.7)

WARNING: CYTOKINE RELEASE SYNDROME and IMMUNEEFFECTOR CELL-ASSOCIATED NEUROTOXICITYSYNDROME
See full prescribing information for complete boxed warning.

--------------------- DOSAGE FORMS AND STRENGTHS---------------------• Injection: 4 mg/0.8 mL in a single-dose vial. Dilute prior to use. (3)• Injection: 48 mg/0.8 mL in a single-dose vial. (3)Cytokine release syndrome (CRS), including serious or life-threatening
reactions, can occur in patients receiving EPKINLY. Initiate treatment
with the EPKINLY step-up dosing schedule to reduce the incidence andseverity of CRS. Withhold EPKINLY until CRS resolves orpermanently discontinue based on severity. (2.1, 2.2, 2.6, 5.1)------------------------------ CONTRAINDICATIONS -----------------------------None. (4)Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS),
including life-threatening and fatal reactions, can occur with
EPKINLY. Monitor patients for neurological signs or symptoms of
ICANS during treatment. Withhold EPKINLY until ICANS resolves
or permanently discontinue based on severity. (2.1, 2.2, 2.6, 5.2)----------------------- WARNINGS AND PRECAUTIONS ----------------------• Infections: Can cause serious or fatal 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 ofreproductive potential of the potential risk to the fetus and to use effective
contraception. (5.5, 8.1, 8.3)--------------------------- INDICATIONS AND USAGE---------------------------EPKINLY is a bispecific CD20-directed CD3 T-cell engager indicated for thetreatment of adult patients with relapsed or refractory diffuse large B-cell
lymphoma (DLBCL), not otherwise specified, including DLBCL arising fromindolent lymphoma, and high-grade B-cell lymphoma after two or more lines
of systemic therapy. (1)------------------------------ ADVERSE REACTIONS -----------------------------The most common (≥ 20%) adverse reactions are cytokine release syndrome,
fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal
pain, nausea, and diarrhea. The most common Grade 3 to 4 laboratory
abnormalities (≥ 10%) are decreased lymphocyte count, decreased neutrophil
count, decreased white blood cell count, decreased hemoglobin, and decreased
platelets. (6.1)

This indication is approved under accelerated approval based on response rateand durability of response. Continued approval for this indication may becontingent upon verification and description of clinical benefit in aconfirmatory trial(s).

To report SUSPECTED ADVERSE REACTIONS, contact
Genmab US, Inc. at 1-855-4GENMAB (1-855-443-6622) or FDA at 1-800FDA-1088 or www.fda.gov/medwatch.

----------------------- DOSAGE AND ADMINISTRATION ----------------------•For subcutaneous injection only. (2.2)•
Recommended Dosage: (2.2)
Cycle of treatmentaCycle 1
Cycles 2 and 3
Cycles 4 to 9
Cycle 10 and beyondaCycle = 28 days

Day oftreatment

1
8
15
22
1, 8, 15 and 22
1 and 15
1

Dose of EPKINLY

See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 5/2023

Step-up dose 1
0.16 mg
Step-up dose 2
0.8 mgFirst full dose
48 mg
48 mg
48 mg
48 mg
48 mg

FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: CYTOKINE RELEASE SYNDROME and
IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITYSYNDROME1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Important Dosing Information
2.2 Recommended Dosage
2.3 Restarting EPKINLY after Dosage Delay
2.4 Recommended Premedications
2.5 Recommended Prophylaxis
2.6 Dosage Modifications and Management of Adverse Reactions
2.7 Preparation and Administration
3
DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS5WARNINGS AND PRECAUTIONS
5.1 Cytokine Release Syndrome
5.2 Immune Effector Cell-Associated Neurotoxicity Syndrome
5.3 Infections
5.4 Cytopenias
5.5 Embryo-Fetal Toxicity
6
ADVERSE REACTIONS

Reference ID: 5176689----------------------- USE IN SPECIFIC POPULATIONS ----------------------Lactation: Advise not to breastfeed. (8.2)

7
8

11
12

13
14
16
17

6.1 Clinical Trials Experience
DRUG INTERACTIONSUSE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.6 Immunogenicity
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIESHOW SUPPLIED/STORAGE AND HANDLINGPATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are notlisted.

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

FULL PRESCRIBING INFORMATIONWARNING: CYTOKINE RELEASE SYNDROME AND IMMUNE EFFECTOR
CELL-ASSOCIATED NEUROTOXICITY SYNDROME
Cytokine release syndrome (CRS), including serious or life-threatening reactions, canoccur in patients receiving EPKINLY. Initiate treatment with the EPKINLY step-up
dosing schedule to reduce the incidence and severity of CRS. Withhold EPKINLY until
CRS resolves or permanently discontinue based on severity [see Dosage andAdministration (2.1, 2.2, 2.6) and Warnings and Precautions (5.1)].
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), including lifethreatening and fatal reactions, can occur with EPKINLY. Monitor patients forneurological signs or symptoms of ICANS during treatment. Withhold EPKINLY until
ICANS resolves or permanently discontinue based on severity [see Dosage andAdministration (2.1, 2.2, 2.6) and Warnings and Precautions (5.2)].
1

INDICATIONS AND USAGEEPKINLY 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)]. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in a confirmatory trial(s).
2DOSAGE AND ADMINISTRATION

2.1

Important Dosing Information•

Administer EPKINLY to well-hydrated patients.

•

Premedicate before each dose in Cycle 1 [see Dosage and Administration (2.4)].

•

EPKINLY should only be administered by a qualified healthcare professional withappropriate medical support to manage severe reactions such as cytokine release syndrome(CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [see Warnings
and Precautions (5.1, 5.2)].

•

Administer EPKINLY subcutaneously according to the dosage schedule in Table 1 to reducethe incidence and severity of CRS. Due to the risk of CRS and ICANS, patients should be
hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg [seeDosage and Administration (2.2) and Warnings and Precautions (5.1, 5.2)].

Reference ID: 5176689

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For current labeling information, please visit https://www.fda.gov/drugsatfda

2.2

Recommended Dosage

EPKINLY is for subcutaneous injection only.
The recommended dosage schedule for EPKINLY is provided in Table 1. Administer EPKINLY
in 28-day cycles until disease progression or unacceptable toxicity.
Table 1: EPKINLY Dosage Schedule
Cycle of treatmenta
Day of treatment
1
Cycle 1
Cycles 2 and 3
Cycles 4 to 9
Cycle 10 and beyond
a

8
15
22
1, 8, 15 and 22
1 and 15
1

Dose of EPKINLY
Step-up dose 1
0.16 mg
Step-up dose 2First full dose

0.8 mg
48 mg
48 mg
48 mg
48 mg
48 mg

Cycle = 28 days

2.3 Restarting EPKINLY after Dosage Delay
If a dose of EPKINLY is delayed, restart therapy based on the recommendations made in Table 2
and resume the treatment schedule accordingly [see Dosage and Administration (2.2)].
Table 2: Recommendations for Restarting Therapy with EPKINLY After Dosage Delay
Last DoseTime Since the Last
Action for Next Dose(s)aAdministered
Dose Administered0.16 mg onMore than 8 days
Repeat 0.16 mg, then administer 0.8 mg the
Cycle 1 Day 1
following week, followed by two weekly dosesof 48 mg. Then resume the planned dosage
schedule beginning with Day 1 of thesubsequent cycle.
0.8 mg on
14 days or less
Administer 48 mg then resume the
Cycle 1 Day 8
recommended dosage schedule.
More than 14 days
Repeat 0.16 mg, then administer 0.8 mg thefollowing week, followed by two weekly dosesof 48 mg. Then resume the planned dosage
schedule beginning with Day 1 of thesubsequent cycle.
48 mg on Cycle 1 6 weeks or less
Administer 48 mg, then resume theDay 15 onwards
recommended dosage schedule.
More than 6 weeks
Repeat 0.16 mg, then administer 0.8 mg thefollowing week, followed by two weekly dosesof 48 mg. Then resume the planned dosage

Reference ID: 5176689

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Last Dose
AdministeredTime Since the Last
Dose Administered

Action for Next Dose(s)aschedule beginning with Day 1 of thesubsequent cycle.

Administer pretreatment medication prior to EPKINLY dose and monitor patients accordingly [see Dosage andAdministration (2.4, 2.6)].
a2.4

Recommended Premedications

Administer premedications as outlined in Table 3 to reduce the risk of CRS [see Warnings andPrecautions (5.1)].
Table 3: EPKINLY Premedications
Patients
requiring
Premedication
Cycle
premedication
Cycle 1
All patients• Prednisolone (100 mg oral
or intravenous) or
Dexamethasone (15 mg oral
or intravenous) or equivalent••
Cycle 2+aPatients who
experienced
Grade 2 or 3a
CRS with
previous dose•

Diphenhydramine (50 mg
oral or intravenous) or
equivalentAcetaminophen (650 to
1,000 mg oral)
Prednisolone (100 mg oral
or intravenous) or
Dexamethasone (15 mg oral
or intravenous) or equivalent

Administration
•

•

•

•

•

Patients will be permanently discontinued from EPKINLY after Grade 4 CRS.

Reference ID: 5176689

30-120 minutes prior toeach weekly
administration of
EPKINLY
And for three consecutive
days following eachweekly administration of
EPKINLY in Cycle 1
30-120 minutes prior toeach weekly
administration of
EPKINLY
30-120 minutes prior tonext administration of
EPKINLY after a Grade 2
or 3a CRS event
And for three consecutive
days following the next
administration of
EPKINLY until
EPKINLY is given
without subsequent CRSof Grade 2 or higher

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For current labeling information, please visit https://www.fda.gov/drugsatfda

2.5

Recommended Prophylaxis

Pneumocystis jirovecii pneumonia (PJP)
Provide PJP prophylaxis prior to starting treatment with EPKINLY.
Herpes virus
Consider initiating prophylaxis against herpes virus prior to starting EPKINLY to prevent herpes
zoster reactivation.
2.6

Dosage Modifications and Management of Adverse Reactions

See Tables 4 and 5 for recommended actions for adverse reactions of CRS and ICANS,
respectively. See Table 6 for recommended actions for other adverse reactions following
administration of EPKINLY.
Cytokine Release Syndrome (CRS)
Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate forand treat other causes of fever, hypotension, and hypoxia.
If CRS is suspected, withhold EPKINLY until CRS resolves. Manage according to therecommendations in Table 4 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 4: Recommendations for Management of Cytokine Release Syndrome
GradeaPresenting Symptoms
Actionsb
Grade 1 Temperature ≥ 100.4°F (38°C)• Withhold EPKINLY and manage
per current practice guidelines.
• Ensure CRS symptoms are resolved
prior to next dose of EPKINLY.c
Grade 2

Reference ID: 5176689

Temperature ≥ 100.4°F (38°C)b with:•

Hypotension not requiring vasopressors•

and/or•Hypoxia requiring low-flow oxygene bynasal cannula or blow-by.

•

Withhold EPKINLY and manage
per current practice guidelines.
Ensure CRS symptoms are resolved
prior to next dose of EPKINLY.c
Administer premedicationd prior tonext dose of EPKINLY.
For the next dose of EPKINLY,
monitor more frequently andconsider hospitalization.

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GradeaGrade 3Presenting Symptoms
Temperature ≥ 100.4°F (38°C)b with:
Hypotension requiring a vasopressor(with or without vasopressin)
and/orHypoxia requiring high-flow oxygene
by nasal cannula, face mask, nonrebreather mask, or Venturi mask.

Grade 4Temperature ≥ 100.4°F (38°C)b with:
Hypotension requiring multiple
vasopressors (excluding vasopressin)
and/orActions• 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.c• Administer premedicationd prior tonext dose of EPKINLY.
• Hospitalize for the next dose of
EPKINLY.
Recurrent Grade 3 CRS• Permanently discontinue
EPKINLY.
• Manage CRS per current practiceguidelines and provide supportive
therapy, which may include
intensive care.
• Permanently discontinue
EPKINLY.
• Manage CRS per current practiceguidelines and provide supportive
therapy, which may include
intensive care.

Hypoxia requiring oxygen by positive
pressure (e.g., CPAP, BiPAP,
intubation and mechanical ventilation).

Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS.
Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow thesemanagement guidelines.
cRefer to Table 2 for information on restarting EPKINLY after dosage delays [see Dosage and Administration(2.3)].
d
If Grade 2 or 3 CRS occurs with the second full dose (48 mg) or beyond, administer CRS premedications witheach subsequent dose until a EPKINLY dose is given without subsequent CRS of Grade 2 or higher. Refer toTable 3 for additional information on premedication.
e
Low-flow oxygen defined as oxygen delivered at < 6L/minute; high-flow oxygen defined as oxygen delivered at≥ 6 L/minute.
abImmune 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 othercauses of neurologic symptoms. Provide supportive therapy, which may include intensive care,for ICANS [see Warnings and Precautions (5.2)]. Manage ICANS according to therecommendations in Table 5 and consider further management per current practice guidelines.

Reference ID: 5176689

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Table 5: Recommendations for Management of Immune Effector Cell-Associated
Neurotoxicity Syndrome
GradeaPresenting Symptomsb
Actionsc
Grade 1 ICE score 7-9 ,• Withhold EPKINLY until ICANS
resolves.e
Or depressed level of• Monitor neurologic symptoms andconsciousnessd: awakens
consider consultation with neurologist andspontaneously.
other specialists for further evaluation andmanagement, including consideration forstarting non-sedating, anti-seizure
medicines for seizure prophylaxis.
Grade 2 ICE score 3-6c,• Withhold EPKINLY until ICANS
resolves.e
Or depressed level of• Administer dexamethasonef 10 mg
dconsciousness : awakens to voice.
intravenously every 6 hours. Continue
dexamethasone use until resolution to
Grade 1 or less, then taper.
• Monitor neurologic symptoms andconsider consultation with neurologist andother specialists for further evaluation andmanagement, including consideration forstarting non-sedating, anti-seizure
medicines for seizure prophylaxis.
cGrade 3 ICE score 0-2 ,First Occurrence of Grade 3 ICANS• Withhold EPKINLY until ICANSOr depressed level ofresolves.edconsciousness : awakens only to• Administer dexamethasonef 10 mg
tactile stimulus,
intravenously every 6 hours. Continue
dexamethasone use until resolution to
Or seizures,d either:
Grade 1 or less, then taper.
• Any clinical seizure, focal or• Monitor neurologic symptoms andgeneralized, that resolves
consider consultation with neurologist andrapidly, orother specialists for further evaluation and• Non-convulsive seizures on
management, including consideration forelectroencephalogram (EEG)
starting non-sedating, anti-seizurethat resolve with intervention,
medicines for seizure prophylaxis.
• Provide supportive therapy, which may
Or raised intracranial pressure:include intensive care.
focal/local edema on
Recurrent Grade 3 ICANS
neuroimaging.d• Permanently discontinue EPKINLY• Administer dexamethasonef 10 mg
intravenously every 6 hours. Continue
dexamethasone use until resolution to
Grade 1 or less, then taper.

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GradeaPresenting Symptomsb••
Grade 4

ICE score 0c,
Or depressed level ofconsciousnessd: either:• Patient is unarousable or
requires vigorous or repetitive
tactile stimuli to arouse, or• Stupor or coma
Or seizures,d either:• Life-threatening prolonged
seizure (> 5 minutes), or• Repetitive clinical or electricalseizures without return tobaseline in between,
Or motor findingsd:• Deep focal motor weakness,such as hemiparesis orparaparesis,
or raised intracranialpressure/cerebral edema,d withsigns/symptoms such as:• Diffuse cerebral edema on
neuroimaging, or• Decerebrate or decorticate
posturing, or• Cranial nerve VI palsy, or• Papilledema, or• Cushing’s triad.

•
•

•

•

•

Actions
Monitor neurologic symptoms andconsider consultation with neurologist andother specialists for further evaluation andmanagement, including consideration forstarting non-sedating, anti-seizure
medicines for seizure prophylaxis.
Provide supportive therapy, which may
include intensive care.
Permanently discontinue EPKINLY.
Administer dexamethasonef 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 andconsider consultation with neurologist andother specialists for further evaluation andmanagement, including consideration forstarting non-sedating, anti-seizure
medicines for seizure prophylaxis.
Provide supportive therapy, which may
include intensive care.

Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS.
Management is determined by the most severe event, not attributable to any other cause.
c
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 toclock, 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 backwardsabReference ID: 5176689

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GradeaPresenting Symptomsb

Actionsfrom 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0
points.
d
Not attributable to any other cause.
e
See Table 2 for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration(2.3)].
f
All references to dexamethasone administration are dexamethasone or equivalent.

Table 6: Recommended Dosage Modifications for Other Adverse Reactions
Adverse Reaction1
Severity1
ActionInfections [see Warnings andGrades 1-4• Withhold EPKINLY in
Precautions (5.3)]
patients with active infection,
until the infection resolves.2• For Grade 4, consider
permanent discontinuation of
EPKINLY.
Neutropenia [see Warnings
Absolute neutrophil count • Withhold EPKINLY untiland Precautions (5.4)]
less than 0.5 x 109/L
absolute neutrophil count is
0.5 x 109/L or higher.2
Thrombocytopenia [seePlatelet count• Withhold EPKINLY until
Warnings and Precautions
less than 50 x 109/L
platelet count is 50 x 109/L or(5.4)]
higher.2
Other Adverse Reactions [seeGrade 3 or higher• Withhold EPKINLY until theAdverse Reactions (6.1)]
toxicity resolves to Grade 1 orbaseline.2
Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version
5.0.
2
See Table 2 for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration(2.3)].
1

2.7

Preparation and Administration

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 thedosage 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.
Preparation of EPKINLY
Use aseptic technique to prepare EPKINLY. Filtration of the diluted solution is not required.

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Preparation instructions for 0.16 mg and 0.8 mg dose of EPKINLY
0.16 mg Dose Preparation Instructions (2 dilutions required)
Use an appropriately sized syringe, vial, and needle for each transfer step.
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.
1.

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, USP 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, USP 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 dosea. Withdraw 1 mL of the diluted EPKINLY from the Dilution B vial into a syringe.

5.

Label syringea. 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)
Use an appropriately sized syringe, vial, and needle for each transfer step.
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.
1.

2.

Reference ID: 5176689

Perform dilution
a. Label an appropriately sized empty vial as “Dilution A”.

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Transfer 0.8 mL of EPKINLY into the Dilution A vial.
c. Transfer 4.2 mL of 0.9% Sodium Chloride Injection, USP 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.
b.

3.

Withdraw dosea. Withdraw 1 mL of the diluted EPKINLY from the Dilution A vial into a syringe.

4.

Label syringea. Label the syringe with the dose strength (0.8 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 dosea. Withdraw 0.8 mL of EPKINLY into a syringe.
3. Label syringea. Label the syringe with the dose strength (48 mg) and the time of day.
Discard the vial containing unused EPKINLY.
Diluted EPKINLY Storage
Use diluted EPKINLY solution 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. Allow EPKINLY
solution to equilibrate to room temperature for no more than 1 hour before administration.
Discard unused EPKINLY solution beyond the allowable storage time.
Administration
Inject the required volume of EPKINLY into the subcutaneous tissue of the lower part of theabdomen (preferred injection site) or the thigh. Change of injection site from the left or right sideor 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 notintact.

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3

DOSAGE FORMS AND STRENGTHSEPKINLY is a clear to slightly opalescent, colorless to slightly yellow solution for subcutaneous
injection:••

Injection: 4 mg/0.8 mL in a single-dose vial, which must be diluted prior to use
Injection: 48 mg/0.8 mL in a single-dose vial

4

CONTRAINDICATIONS

None.
5

WARNINGS AND PRECAUTIONS

5.1

Cytokine Release Syndrome

EPKINLY can cause CRS, including serious or life-threatening reactions [see Adverse Reactions(6.1)].
Cytokine release syndrome occurred in 51% of patients receiving EPKINLY at therecommended dose in the clinical trial, with Grade 1 CRS occurring in 37%, Grade 2 in 17%,and Grade 3 in 2.5% of patients. Recurrent CRS occurred in 16% of patients. Of all the CRS
events, most (92%) occurred during Cycle 1. In Cycle 1, 9% of CRS events occurred after the
0.16 mg dose on Cycle 1 Day 1, 16% after the 0.8 mg dose on Cycle 1 Day 8, 61% after the
48 mg dose on Cycle 1 Day 15, and 6% after the 48 mg dose on Cycle 1 Day 22.
The median time to onset of CRS from the most recent administered EPKINLY dose across all
doses was 24 hours (range: 0 to 10 days). The median time to onset after the first full 48 mg dosewas 21 hours (range: 0 to 7 days). CRS resolved in 98% of patients and the median duration of
CRS events was 2 days (range: 1 to 27 days).
In patients who experienced CRS, the signs and symptoms included pyrexia, hypotension,
hypoxia, dyspnea, chills, and tachycardia. Concurrent neurological adverse reactions associatedwith CRS occurred in 2.5% of patients and included headache, confusional state, tremors,dizziness, and ataxia.
Initiate therapy according to EPKINLY step-up dosing schedule. Administer pretreatment
medications to reduce the risk of CRS and monitor patients for potential CRS following
EPKINLY accordingly. Following administration of the first 48 mg dose, patients should be
hospitalized for 24 hours [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 practiceguidelines, and administer supportive care as appropriate. Withhold or discontinue EPKINLY
based on the severity of CRS [see Dosage and Administration (2.6)].

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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)].
Immune Effector Cell-Associated Neurotoxicity Syndrome occurred in 6% (10/157) of patients
receiving EPKINLY at the recommended dose in the clinical trial, 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 toonset of ICANS of 16.5 days (range: 8 to 141 days) from the start of treatment. Relative to themost 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. Clinical manifestations of ICANS included,
but were not limited to, confusional state, lethargy, tremor, dysgraphia, aphasia, andnon-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, andpatients 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 serious and fatal infections [see Adverse Reactions (6.1)].
In the clinical trial, serious infections, including opportunistic infections, were reported in 15%
of patients treated with EPKINLY at the recommended dose with Grade 3 or 4 infections in 14%
and fatal infections in 1.3%. The most common Grade 3 or greater infections were sepsis,
COVID-19, urinary tract infection, pneumonia, and upper respiratory tract infection.
Monitor patients for signs and symptoms of infection prior to and during treatment with
EPKINLY and treat appropriately. Avoid administration of EPKINLY in patients with active
infections. Provide PJP prophylaxis prior to initiating treatment with EPKINLY; consider
initiating prophylaxis against herpes virus prior to starting EPKINLY [see Dosage andAdministration (2.5)].

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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, anemia, andthrombocytopenia [see Adverse Reactions (6.1)].
Among patients who received the recommended dosage in the clinical trial, Grade 3 or 4
decreased neutrophils occurred in 32%, decreased hemoglobin in 12%, and decreased platelets in
12% of patients. Febrile neutropenia occurred in 2.5%.
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 apregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females ofreproductive 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)].
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)].
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 trialsof 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 withrelapsed or refractory LBCL after two or more lines of systemic therapy, including DLBCL not

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otherwise specified, DLBCL arising from indolent lymphoma, high grade B-cell lymphoma, andother B-cell lymphomas [see Clinical Studies (14)]. A total of 157 patients received EPKINLY
via subcutaneous injection until disease progression or unacceptable toxicities according to thefollowing 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% male, and 97%
had an ECOG performance status of 0 or 1. Race was reported in 133 (85%) patients; of thesepatients, 61% were White, 19% were Asian, and 0.6% were Native Hawaiian or Other PacificIslander. There were no Black or African American or Hispanic or Latino patients treated in theclinical 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 organtransplant, 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 COVID19 (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.

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Table 7 summarizes the adverse reactions in EPCORE NHL-1.
Table 7: Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory LBCL Who
Received EPKINLY in EPCORE NHL-1
EPKINLY(N=157)Adverse Reaction§
All Grades
Grade 3 or 4(%)(%)
Immune system disorders
Cytokine release syndrome*51
2.5#
General disorders and administration site conditions
Fatiguea
29
2.5#
Injection site reactionsb
27
0
Pyrexia
24
0
c
Edema
14
1.9#
Musculoskeletal and connective tissue disorders
Musculoskeletal paind
28
1.3#
Gastrointestinal disorders
Abdominal paine
23
1.9#
Diarrhea
20
0
Nausea20
1.3#
Vomiting
12
0.6#
Skin and subcutaneous disorders
Rashf
15
0.6#
Nervous system disorder
Headache13
0.6#
Metabolism and nutrition disorders
Decreased appetite
120.6#
Cardiac disorders
Cardiac arrhythmiasg
100.6#

Adverse reactions were graded based on CTCAE Version 5.0
Only grade 3 adverse reactions occurred.
*
CRS was graded using ASTCT consensus criteria (Lee et al., 2019).
a
Fatigue includes asthenia, fatigue, lethargy.
b
Injection site reactions 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.
c
Edema includes edema, edema peripheral, face edema, generalized edema, peripheral swelling.
dMusculoskeletal 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.
eAbdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper,
abdominal tenderness.
fRash includes dermatitis bullous, erythema, palmar erythema, penile erythema, rash, rash erythematous, rash
maculo-papular, rash pustular, recall phenomenon, seborrheic dermatitis, skin exfoliation.
g
Cardiac arrhythmias includes bradycardia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles,
supraventricular tachycardia, tachycardia.
§#

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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 8 summarizes laboratory abnormalities in EPCORE NHL-1.
Table 8: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline inPatients with Relapsed or Refractory LBCL Who Received EPKINLY in EPCORE NHL-1
Laboratory Abnormality*
Hematology
Lymphocyte count decreased
Hemoglobin decreased
White blood cells decreased
Neutrophils decreased
Platelets decreased
Chemistry
Sodium decreased
Phosphate decreased2
Aspartate aminotransferase increased
Alanine aminotransferase increased
Potassium decreased
Magnesium decreased
Creatinine increased
Potassium increased

EPKINLY1
All Grades (%)

Grade 3 or 4 (%)

87
62
53
50
48

77
12
22
32
12

56
56
48
45
34
31
24
21

2.6
N/A
4.6
5.3
5.3
0
3.3
1.3

Laboratory abnormalities were graded based on CTCAE Version 5.0
The denominator used to calculate the rate varied from 146 to 153 based on the number of patients with abaseline value and at least one post-treatment value.
2
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).
*
1

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 on Cycle 1
Day 1 and up to 14 days after the first 48 mg dose on Cycle 1 Day 15, and during and after CRS[see Warnings and Precautions (5.1)].

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8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary
Based on the mechanism of action, EPKINLY may cause fetal harm when administered to apregnant 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 ordevelopmental 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 andthe 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 andmiscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
8.2

Lactation

Risk Summary
There is no information regarding the presence of epcoritamab-bysp in human milk, the effect on
the breastfed child, or milk production. Because maternal IgG is present in human milk, andthere is potential for epcoritamab-bysp absorption leading to serious adverse reactions in abreastfed child, advise women not to breastfeed during treatment with EPKINLY and for
4 months after the last dose.
8.3

Females and Males of Reproductive Potential

EPKINLY may cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating EPKINLY.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with
EPKINLY and for 4 months after the last dose.

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8.4

Pediatric Use

The safety and efficacy of EPKINLY in pediatric patients have not been established.
8.5

Geriatric Use

In patients with relapsed or refractory LBCL who received EPKINLY in the clinical trial, 49%
were 65 years of age or older, and 19% were 75 years of age or older. No clinically meaningful
differences in safety or efficacy were observed between patients 65 years of age or older
compared with younger adult patients.
11

DESCRIPTION

Epcoritamab-bysp is a bispecific CD20-directed CD3 T-cell engager; it is a humanized bispecific
IgG1 antibody. Epcoritamab-bysp is manufactured in Chinese hamster ovary (CHO) cells using
recombinant DNA technology and has an approximate molecular weight of 149 kDa.
EPKINLY (epcoritamab-bysp) injection for subcutaneous use is a sterile, preservative-free, clear
to slightly opalescent, colorless to slightly yellow solution, free of visible particles.
Each single-dose 4 mg/0.8 mL vial contains epcoritamab-bysp (4 mg), acetic acid (0.19 mg),polysorbate 80 (0.32 mg), sodium acetate (1.7 mg), sorbitol (21.9 mg) and Water for Injection,
USP. The pH is 5.5.
Each single-dose 48 mg/0.8 mL vial contains epcoritamab-bysp (48 mg), acetic acid (0.19 mg),polysorbate 80 (0.32 mg), sodium acetate (1.7 mg), sorbitol (21.9 mg) and Water for Injection,
USP. The pH is 5.5.
12

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action
Epcoritamab-bysp is a T-cell engaging bispecific antibody that binds to the CD3 receptor
expressed on the surface of T-cells and CD20 expressed on the surface of lymphoma cells andhealthy B-lineage cells.
In vitro, epcoritamab-bysp activated T-cells, caused the release of proinflammatory cytokines,
and induced lysis of B-cells.
12.2 Pharmacodynamics
Circulating B Cell Count
Circulating B cells decreased to undetectable levels (< 10 cells/microliter) after administration of
the approved recommended dosage of EPKINLY in patients who had detectable B cells at

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treatment initiation by Cycle 1 Day 15 (after the first full dose of 48 mg) and the depletion was
sustained while patients remained on treatment.
Cytokine Concentrations
Plasma concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α, and IFN-γ) were measured.
Transient elevation of circulating cytokines was observed at dose levels of 0.04 mg and above.
After administration of the approved recommended dosage of EPKINLY, the cytokine levels
increased within 24 hours after the first dose on Cycle 1 Day 1, reached maximum levels after
the first 48 mg dose on Cycle 1 Day 15, and returned to baseline prior to the next 48 mg full doseon Cycle 1 Day 22.
12.3 Pharmacokinetics
Pharmacokinetic (PK) parameters were evaluated at the approved recommended dosage (48 mg)
and are presented as geometric mean (CV%) unless otherwise specified.
Epcoritamab-bysp area under the concentration-time curve (AUC) increased more thanproportionally over a full dosage range from 1.5 to 60 mg (0.03125 to 1.25 times the approved
recommended dosage).
Epcoritamab-bysp maximum concentration (11.1 mcg/mL [41.5%]) is achieved after the firstdose of the Q2W regimen (i.e., after the 11th dose of 48 mg at the first dose of Cycle 4). PK
exposures are summarized for the recommended dosage of EPKINLY in Table 9.
Table 9: Exposure Parameters of Epcoritamab-bysp in Subjects with Relapsed or
Refractory LBCL
Cavg
Cmax
Ctrough(mcg/mL)¹ (mcg/mL)¹ (mcg/mL)¹
First full 48 mg dose
1.6 (72.4)
2.2 (70.0)
1.7 (74.0)
End of weekly dosing (end of Cycle 3)
9.9 (45.1)
10.8 (41.7)
8.4 (53.3)
End of every 2-week dosing (end of Cycle 9)
5.9 (49.3)
7.5 (41.1)
4.1 (73.9)
Steady state² with every 4-week dosing
2.7 (69.5)
4.8 (51.6)
1.2 (130)¹ Values are geometric mean with geometric CV%² Steady state values are approximated at Cycle 15 (Week 60)

Absorption
The median (range) Tmax of epcoritamab-bysp after the first full dose and end of the weekly
dosing regimen (end of Cycle 3) treatment doses were 4 (0.3 to 7) days and 2.3 (0.3 to 3.2) days,
respectively.
Distribution
The apparent total volume of distribution is 25.6 L (82%).

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Elimination
The half-life of full dose epcoritamab-bysp (48 mg) was approximately 22 days (58%) at the endof Cycle 3, with apparent total clearance of approximately 0.53 L/day (40%) after the end of
Cycle 3.
Metabolism
Epcoritamab-bysp is expected to be metabolized into small peptides by catabolic pathways.
Specific Populations
No clinically significant differences in the PK of epcoritamab-bysp were observed based on age(20 to 89 years), sex, race (White or Asian), mild to moderate renal impairment (creatinine
clearance [CLcr] 30 to < 90 mL/min as estimated by Cockcroft-Gault formula), and mild hepatic
impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN and
any AST) after accounting for differences in bodyweight.
The effects of severe renal impairment (CLcr 15 to < 30 mL/min), end-stage renal disease (CLcr< 15 mL/min), or moderate to severe hepatic impairment (total bilirubin > 1.5 times ULN and
any AST) on the PK of epcoritamab-bysp are unknown.
Body Weight
In patients who received the recommended dosage of EPKINLY, Cycle 1 median average
concentration was 13% lower in the higher body weight (BW) group (85 to 144 kg) and 37%
higher in the lower BW group (39 to 65 kg) compared to patients with BW of 65 to less than
85 kg.
Drug Interaction Studies
No clinical studies evaluating the drug interaction potential of epcoritamab-bysp have been
conducted.
12.6 Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity andspecificity of the assay. Differences in assay methods preclude meaningful comparisons of theincidence of anti-drug antibodies (ADA) in the study described below with the incidence of
ADA in other studies, including those of epcoritamab-bysp.
Anti-epcoritamab-bysp antibodies developed in 2.6% of patients (4 of 156) treated with
EPKINLY at the recommended dosage during treatment in Study EPCORE NHL-1 (up to
10 cycles) [see Clinical Studies (14)] using an electrochemiluminescence immunoassay(ECLIA). Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on
the PK, pharmacodynamics, safety, and effectiveness of epcoritamab-bysp is unknown.

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13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or genotoxicity studies have been conducted with epcoritamab-bysp.
No dedicated studies have been conducted to evaluate the effects of epcoritamab-bysp on
fertility.
14

CLINICAL STUDIESThe efficacy of EPKINLY was evaluated in EPCORE NHL-1 (Study GCT3013-01;
NCT03625037), an open-label, multi-cohort, multicenter, single-arm trial in 157 patients withrelapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic
therapy. The study excluded patients with CNS involvement of lymphoma, allogeneic HSCT or
solid organ transplant, ongoing active infection, and any patients with known impaired T-cell
immunity. Patients received EPKINLY monotherapy as a subcutaneous injection 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

Patients continued to receive EPKINLY until disease progression or unacceptable toxicity. In thesetting of a suspected tumor flare reaction, continued treatment was permitted.
The efficacy population includes 148 patients with DLBCL, not otherwise specified (NOS),
including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma. Of the
148 patients, the median age was 65 years (range: 22 to 83), 62% were male, 97% had an ECOG
performance status of 0 or 1, and 3% had an ECOG performance status of 2. Race was reported
in 125 (84%) patients; of these patients, 61% were White, 20% were Asian, and 0.7% 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 diagnosis was DLBCLNOS in 86%, including 27% with DLBCL transformed from indolent lymphoma, and high-grade
B-cell lymphoma in 14%. The median number of prior therapies was 3 (range: 2 to 11), with30% receiving 2 prior therapies, 30% receiving 3 prior therapies, and 40% receiving 4 or moreprior therapies. Eighteen percent had prior autologous HSCT, and 39% had prior chimericantigen receptor (CAR) T-cell therapy. Eighty-two percent of patients had disease refractory tolast therapy and 29% of patients were refractory to CAR T-cell therapy.
Efficacy was established based on overall response rate (ORR) determined by Lugano 2014
criteria as assessed by Independent Review Committee (IRC) and duration of response. The
efficacy results are summarized in Table 10.

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Table 10: Efficacy Results in EPCORE NHL-1 in Patients with DLBCL and High-grade Bcell Lymphoma
EPKINLY
Endpointa(N=148)
ORRb, n (%)
90 (61)(95% CI)(52.5, 68.7)
CR, n (%)
56 (38)(95% CI)(30.0, 46.2)
PR, n (%)
34 (23)(95% CI)(16.5, 30.6)
DOR
Median (95% CI), months
15.6 (9.7, NR)c9-month estimate % (95% CI)
63 (51.5, 72.4)
ORR = overall response rate; CI = confidence interval; CR = complete response; PR = partial response; DOR =duration of response; NR = not reached.
aDetermined by Lugano criteria (2014) as assessed by independent review committee (IRC).
b
Early response assessments were evaluated in the context of potential flare reactions. Of 90 patients whoachieved an objective response, 9 patients had early flare reactions identified with objective response
demonstrated on subsequent imaging per Lugano criteria.
cKaplan-Meier estimate.

The median time to response was 1.4 months (range: 1 to 8.4 months). Among responders, themedian follow-up for DOR was 9.8 months (range: 0.0 to 17.3 months).
16

HOW SUPPLIED/STORAGE AND HANDLINGHow Supplied
EPKINLY (epcoritamab-bysp) injection is a sterile, preservative-free, clear to slightly
opalescent, colorless to slightly yellow solution, free of visible particles, supplied in glass vials
as follows:
Carton contents

NDC number

One 4 mg/0.8 mL single-dose vial

NDC 82705-002-01

One 48 mg/0.8 mL single-dose vial

NDC 82705-010-01

The vial stopper is not made with natural rubber latex.
Storage and HandlingStore refrigerated at 2°C to 8°C (36°F to 46°F). Keep in the original carton to protect from light.
Do not freeze. Do not shake.
17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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Cytokine Release Syndrome (CRS)
Inform patients of the risk of CRS, and to immediately contact their healthcare provider should
signs and symptoms associated with CRS (e.g., pyrexia, hypotension, hypoxia, chills,
tachycardia, headache, and dyspnea) occur at any time. Advise patients that they should be
hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg. Advise
patients who experience symptoms that impair consciousness not to drive and refrain fromoperating heavy or potentially dangerous machinery until events resolve [see Warnings andPrecautions (5.1)].
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
Advise patients of the risk of ICANS, to immediately contact their healthcare provider 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 [see Warnings and Precautions (5.2)].
Infections
Advise patients of the risk of serious infections, and to contact their healthcare professional forsigns or symptoms of serious infection [see Warnings and Precautions (5.3)].
Cytopenias
Discuss the signs and symptoms associated with cytopenias, including neutropenia and febrileneutropenia, anemia, and thrombocytopenia [see Warnings and Precautions (5.4)].
Embryo-Fetal Toxicity
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential
to inform their healthcare provider if they are pregnant or become pregnant [see Use in Specific
Populations (8.1)]. 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 (8.3)].
Lactation
Advise women not to breastfeed during treatment with EPKINLY and for 4 months after the lastdose [see Use in Specific Populations (8.2)].
Manufactured by:
Genmab US, Inc.
Plainsboro, NJ 08536, USA
1-855-4GENMAB (1-855-443-6622)
U.S. License Number: 2293
Marketed by:
Genmab US, Inc.
Plainsboro, NJ 08536

Reference ID: 5176689

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

andAbbVie Inc.
North Chicago, IL 60064
EPKINLY is a trademark owned by Genmab A/S©2023 Genmab A/S

Reference ID: 5176689

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDEEPKINLY™ (ep-KIN-lee)(epcoritamab-bysp)
injection, for subcutaneous use
What is the most important information I should know about EPKINLY?
EPKINLY can cause serious side effects, including:• Cytokine Release Syndrome (CRS). CRS is common during treatment with EPKINLY and can also be serious or
life-threatening. Tell your healthcare provider or get medical help right away if you develop any signs or symptomsof CRS, including:o fever of 100.4°F (38°C) or higher
o headacheo dizziness or light-headednesso confusiono trouble breathingo shaking (tremors)o chills
o problems with balance and movement, such aso fast heartbeat
trouble walking
o feeling anxious
Due to the risk of CRS, you will receive EPKINLY on a “step-up dosing schedule”.
o The step-up dosing schedule is when you receive smaller “step-up” doses of EPKINLY on Day 1 and Day 8
of your first cycle of treatment (Cycle 1).
o You will receive your first full dose of EPKINLY on Day 15 of Cycle 1.
o If your dose of EPKINLY is delayed for any reason, you may need to repeat the “step-up dosing schedule”.
o Before each dose in Cycle 1, you will receive medicines to help reduce your risk of CRS. Your healthcare
provider will decide if you need to receive medicine to help reduce your risk of CRS with future cycles.
o See “How will I receive EPKINLY?” for more information about how you will receive EPKINLY.
• Neurologic problems. EPKINLY can cause serious neurologic problems that can be life-threatening and lead todeath. Neurologic problems may happen days or weeks after you receive EPKINLY. Your healthcare provider may
refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away
if you develop any signs or symptoms of neurologic problems, including:o trouble speaking or writingo muscle weaknesso confusion and disorientationo shaking (tremors)o drowsinesso seizureso tiredness or lack of energy
o memory loss
Due to the risk of CRS and neurologic problems, you should be hospitalized for 24 hours after receiving your firstfull dose of EPKINLY on Day 15 of Cycle 1. Your healthcare provider will monitor you for signs and symptoms of CRS
and neurologic problems during treatment with EPKINLY, as well as other side effects and treat you if needed. Your
healthcare provider may temporarily stop or completely stop your treatment with EPKINLY if you develop CRS,
neurologic problems, or any other side effects that are severe.
See “What are the possible side effects of EPKINLY?” for more information about side effects.
What is EPKINLY?
EPKINLY is a prescription medicine used to treat adults with certain types of diffuse large B-cell lymphoma (DLBCL)
and high-grade B-cell lymphoma that has come back (relapsed) or that did not respond to previous treatment(refractory), and who have already received 2 or more treatments for their cancer.
It is not known if EPKINLY is safe and effective in children.
Before receiving EPKINLY, tell your healthcare provider about all of your medical conditions, including if you:• have an infection.
• are pregnant or plan to become pregnant. EPKINLY may harm your unborn baby.
Females who are able to become pregnant:o Your healthcare provider should do a pregnancy test before you start treatment with EPKINLY.
o You should use effective birth control (contraception) during treatment and for 4 months after your last dose of
EPKINLY.
o Tell your healthcare provider if you become pregnant or think that you may be pregnant during treatment with
EPKINLY.
• are breastfeeding or plan to breastfeed. It is not known if EPKINLY passes into your breast milk. Do notbreastfeed during treatment and for 4 months after your last dose of EPKINLY.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.

Reference ID: 5176689

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How will I receive EPKINLY?
• EPKINLY will be given to you by your healthcare provider as an injection under your skin (subcutaneous injection),
usually in the lower part of your stomach-area (abdomen) or thigh.
• Your EPKINLY treatment schedule is divided into cycles that are usually 28 days (4 weeks) long.
• EPKINLY is usually given every week during Cycles 1 to 3, every 2 weeks during Cycles 4 to 9, and every
4 weeks starting with Cycle 10.
• Your healthcare provider will decide how many treatment cycles you will receive.
• See “What is the most important information I should know about EPKINLY?” for more information about
how you will receive EPKINLY.
What should I avoid while receiving EPKINLY?
Do not drive, operate heavy machinery, or do other dangerous activities if you develop dizziness, confusion, tremors,
sleepiness, or any other symptoms that impair consciousness until your signs and symptoms go away. These may besigns and symptoms of CRS or neurologic problems.
See “What is the most important information I should know about EPKINLY?” for more information about signs
and symptoms of CRS and neurologic problems.
What are the possible side effects of EPKINLY?
EPKINLY can cause serious side effects, including:• See “What is the most important information I should know about EPKINLY?”• Infections. EPKINLY can cause serious infections that may lead to death. Your healthcare provider will check you
for signs and symptoms of infection before and during treatment with EPKINLY. Tell your healthcare provider rightaway if you develop any signs or symptoms of infection during treatment with EPKINLY, including:o fever of 100.4°F (38°C) or higher
o painful rasho cougho sore throato chest paino pain during urinationo tiredness
o feeling weak or generally unwello shortness of breath• Low blood cell counts. Low blood cell counts are common during treatment with EPKINLY and can also be
serious or severe. Your healthcare provider will check your blood cell counts during treatment with EPKINLY.
EPKINLY may cause the following low blood cell counts:o low white blood cell counts (neutropenia). Low white blood cells can increase your risk for infection.
o low red blood cell counts (anemia). Low red blood cells can cause tiredness and shortness of breath.
o low platelet counts (thrombocytopenia). Low platelet counts can cause bruising or bleeding problems.
Your healthcare provider may temporarily stop or completely stop treatment with EPKINLY if you develop certain side
effects.
The most common side effects of EPKINLY include:• tiredness• stomach-area (abdominal) pain
• muscle and bone pain
• nausea• injection site reactions• diarrhea• fever
These are not all the possible side effects of EPKINLY.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about safe and effective use of EPKINLY.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask yourpharmacist or healthcare provider for information about EPKINLY that is written for health professionals.
What are the ingredients in EPKINLY?
Active ingredient: epcoritamab-bysp
Inactive ingredients: acetic acid, polysorbate 80, sodium acetate, sorbitol and Water for Injection.
Manufactured by: Genmab US, Inc., Plainsboro, NJ 08536
U.S. License Number: 2293
Marketed by: Genmab US, Inc., Plainsboro, NJ 08536 and AbbVie Inc., North Chicago, IL 60064
EPKINLY is a trademark owned by Genmab A/S©2023 Genmab A/S
For more information, go to www.EPKINLY.com or call 1-855-4GENMAB (1-855-443-6622)
This Medication Guide has been approved by the U.S. Food and Drug Administration.

Reference ID: 5176689

Issued: May 2023