What is mechanism of action?

mechanism of action is CD3 Receptor Agonists [MoA], CD3-directed Antibody Interactions [MoA], CD20-directed Antibody Interactions [MoA] or Cytochrome P450 Inhibitors [MoA]

Epkinly

(Epcoritamab-Bysp)

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Dosage & Administration

* For subcutaneous injection only. (

2.2 Recommended Dosage

EPKINLY is for subcutaneous injection only.

The recommended DLBCL dosage for Cycle 1 consists of 2 step-up doses, and the recommended FL dosage (monotherapy or in combination with lenalidomide and rituximab) consists of 3 step-up doses.

EPKINLY as Monotherapy:

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

Table 1: EPKINLY Dosage Schedule for Patients with DLBCL or High-grade B-cell Lymphoma
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
DLBCL or High-grade B-cell Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	First full dose	48 mg
		22	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

Table 2: EPKINLY Dosage Schedule for Patients with FL when Given as Monotherapy
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

EPKINLY in Combination with Lenalidomide and Rituximab:

Administer EPKINLY in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurs first.

Table 3: EPKINLY Dosage Schedule in Combination with Lenalidomide and Rituximab for Patients with FL
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15, and 22	48 mg
	Cycles 4 to 12	1	48 mg

Administer EPKINLY in combination with lenalidomide 20 mg (Days 1 to 21 in Cycles 1 to 12) and rituximab 375 mg/m²(Cycles 1 to 5)

[see Clinical Studies (14.2)].

Refer to the lenalidomide prescribing information and rituximab prescribing information for the respective dosage recommendations, including lenalidomide dosage recommendations for patients with renal insufficiency.

)
* Recommended Dosage: (

2.2 Recommended Dosage

EPKINLY is for subcutaneous injection only.

The recommended DLBCL dosage for Cycle 1 consists of 2 step-up doses, and the recommended FL dosage (monotherapy or in combination with lenalidomide and rituximab) consists of 3 step-up doses.

EPKINLY as Monotherapy:

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

Table 1: EPKINLY Dosage Schedule for Patients with DLBCL or High-grade B-cell Lymphoma
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
DLBCL or High-grade B-cell Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	First full dose	48 mg
		22	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

Table 2: EPKINLY Dosage Schedule for Patients with FL when Given as Monotherapy
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

EPKINLY in Combination with Lenalidomide and Rituximab:

Administer EPKINLY in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurs first.

Table 3: EPKINLY Dosage Schedule in Combination with Lenalidomide and Rituximab for Patients with FL
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15, and 22	48 mg
	Cycles 4 to 12	1	48 mg

Administer EPKINLY in combination with lenalidomide 20 mg (Days 1 to 21 in Cycles 1 to 12) and rituximab 375 mg/m²(Cycles 1 to 5)

[see Clinical Studies (14.2)].

)

DLBCL and High-grade B-cell Lymphoma

Cycle Cycle = 28 days	Day	Dose of EPKINLY
Cycle 1	1	Step-up dose 1	0.16 mg
	8	Step-up dose 2	0.8 mg
	15	First full dose	48 mg
	22	48 mg
Cycles 2 and 3	1, 8, 15 and 22	48 mg
Cycles 4 to 9	1 and 15	48 mg
Cycle 10 and beyond	1	48 mg

EPKINLY as Monotherapy for FL

CycleCycle = 28 days	Day	Dose of EPKINLY
Cycle 1	1	Step-up dose 1	0.16 mg
	8	Step-up dose 2	0.8 mg
	15	Step-up dose 3	3 mg
	22	First full dose	48 mg
Cycles 2 and 3	1, 8, 15 and 22	48 mg
Cycles 4 to 9	1 and 15	48 mg
Cycle 10 and beyond	1	48 mg

EPKINLY in Combination with Lenalidomide and Rituximab for FL

CycleCycle = 28 days	Day	Dose of EPKINLY
Cycle 1	1	Step-up dose 1	0.16 mg
	8	Step-up dose 2	0.8 mg
	15	Step-up dose 3	3 mg
	22	First full dose	48 mg
Cycles 2 and 3	1, 8, 15, and 22	48 mg
Cycles 4 to 12	1	48 mg

* Monitor all patients for signs and symptoms of CRS and ICANS. (

2.1 Important Dosing Information

* Certain doses of EPKINLY require

dilution

prior to administration. There are 2 available methods to prepare

diluted

EPKINLY:
* Empty sterile vial method as described in subsection 2.7

[see Dosage and Administration (2.7)]

, or
* Sterile syringe method as described in subsection 2.8

[see Dosage and Administration (2.8)]

.

* Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution.

[see Dosage and Administration (2.9)]

.
* EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS

[see Warnings and Precautions (5.1, 5.2)]

.
* Administer EPKINLY to well-hydrated patients.
* Premedicate before each dose in Cycle 1

[see Dosage and Administration (2.4)]

.
* Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS

[see Dosage and Administration (2.2)]

.
* Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms

[see Dosage and Administration (2.6)]

.
* For patients with DLBCL or high-grade B-cell lymphoma:

Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg

[see Dosage and Administration (2.2)].

For patients with FL:

Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the Cycle 1 Day 22 dosage of 48 mg

[see Dosage and Administration (2.2)

)
* Patients with DLBCL or high-grade B-cell lymphoma should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg. (

2.1 Important Dosing Information

* Certain doses of EPKINLY require

dilution

prior to administration. There are 2 available methods to prepare

diluted

EPKINLY:
* Empty sterile vial method as described in subsection 2.7

[see Dosage and Administration (2.7)]

, or
* Sterile syringe method as described in subsection 2.8

[see Dosage and Administration (2.8)]

.

* Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution.

[see Dosage and Administration (2.9)]

.
* EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS

[see Warnings and Precautions (5.1, 5.2)]

.
* Administer EPKINLY to well-hydrated patients.
* Premedicate before each dose in Cycle 1

[see Dosage and Administration (2.4)]

.
* Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS

[see Dosage and Administration (2.2)]

.
* Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms

[see Dosage and Administration (2.6)]

.
* For patients with DLBCL or high-grade B-cell lymphoma:

Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg

[see Dosage and Administration (2.2)].

For patients with FL:

Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the Cycle 1 Day 22 dosage of 48 mg

[see Dosage and Administration (2.2)

)For patients with FL, assess whether hospitalization or outpatient monitoring is appropriate after administration of the Cycle 1 Day 22 dosage of 48 mg. (

2.1 Important Dosing Information

* Certain doses of EPKINLY require

dilution

prior to administration. There are 2 available methods to prepare

diluted

EPKINLY:
* Empty sterile vial method as described in subsection 2.7

[see Dosage and Administration (2.7)]

, or
* Sterile syringe method as described in subsection 2.8

[see Dosage and Administration (2.8)]

.

* Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution.

[see Dosage and Administration (2.9)]

.
* EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS

[see Warnings and Precautions (5.1, 5.2)]

.
* Administer EPKINLY to well-hydrated patients.
* Premedicate before each dose in Cycle 1

[see Dosage and Administration (2.4)]

.
* Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS

[see Dosage and Administration (2.2)]

.
* Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms

[see Dosage and Administration (2.6)]

.
* For patients with DLBCL or high-grade B-cell lymphoma:

Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg

[see Dosage and Administration (2.2)].

For patients with FL:

Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the Cycle 1 Day 22 dosage of 48 mg

[see Dosage and Administration (2.2)

)
* Administer premedications, post-medications, and prophylaxis as recommended. (

2.4 Recommended Pre- and Post-Administration Medications

Administer pre- and post-administration medications as outlined in Table 6 to reduce the risk of CRS

[see Warnings and Precautions (5.1)]

Table 6: EPKINLY Pre- and Post-Administration Medications
Cycle	Patients requiring medication	Medication	Administration
Cycle 1	All patients	* DexamethasoneDexamethasone is the preferred corticosteroid when available.(15 mg oral or intravenous) or Prednisolone (100 mg oral or intravenous) or equivalent	* 30-120 minutes prior to each weekly administration of EPKINLY * And for three consecutive days following each weekly administration of EPKINLY in Cycle 1
Cycle 1	All patients	* Diphenhydramine (50 mg oral or intravenous) or equivalent * Acetaminophen (650 mg to 1,000 mg oral)	* 30-120 minutes prior to each weekly administration of EPKINLY
Cycle 2+	Patients who experienced Grade 2 or 3Patients will be permanently discontinued from EPKINLY after Grade 4 CRS.CRS with previous dose	* Dexamethasone (15 mg oral or intravenous) or Prednisolone (100 mg oral or intravenous) or equivalent	* 30-120 minutes prior to next administration of EPKINLY after a Grade 2 or 3 CRS event * And for three consecutive days following the next administration of EPKINLY until EPKINLY is given without subsequent CRS of Grade 2 or higher

2.5 Recommended Prophylaxis

Pneumocystis jirovecii pneumonia (PJP)

Provide PJP prophylaxis during treatment with EPKINLY.

Herpesvirus

Consider providing prophylaxis against herpesvirus during treatment with EPKINLY to prevent herpes simplex and herpes zoster.

Thromboprophylaxis

Refer to the lenalidomide prescribing information for recommendations on prophylaxis for venous and arterial thrombotic events.

)
* Dosages of EPKINLY 0.16 mg and 0.8 mg require dilution prior to administration. (

2.7 Preparation of Diluted EPKINLY using the Vial Method

Read this entire section carefully before preparation of EPKINLY. Certain doses of EPKINLY require

dilution

prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to improper dose. This section describes preparation of diluted EPKINLY using empty sterile vial method. For preparation using sterile syringe method, see subsection 2.8

[see Dosage and Administration (2.8)]

EPKINLY is prepared and administered by a healthcare provider as a subcutaneous injection. The administration of EPKINLY takes place over the course of 28-day cycles, following the step-up dosage schedule in Section 2.2.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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

0.16 mg Dose Preparation Instructions (

2 dilutions required

) – Empty Sterile Vial Method

Use an appropriately sized syringe, vial, and needle for each transfer step.

*
*

DO NOT

"Dilution A."

0.8 mL of EPKINLY

Dilution A

4.2 mL of 0.9% Sodium Chloride Injection

Dilution A

"Dilution B."

2 mL of solution

Dilution A

Dilution B

Dilution A

8 mL of 0.9% Sodium Chloride Injection

Dilution B

1 mL of the diluted EPKINLY

Dilution B

a.
1. Prepare EPKINLY vial *
2. Perform first dilution *
3. Perform second dilution *
4. Withdraw dose *
5. Label syringe *

Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.Allow the vial to come to room temperature for no more than 1 hour.Gently swirl the EPKINLY vial.invert, vortex, or vigorously shake the vial.Label an appropriately sized empty vial asTransferinto thevial.Transferinto thevial.The initially diluted solution contains 0.8 mg/mL of EPKINLY.Gently swirl thevial for 30 to 45 seconds.Label an appropriately sized empty vial asTransferfrom thevial into thevial. Thevial is no longer needed.Transferinto thevial to make a final concentration of 0.16 mg/mL.Gently swirl thevial for 30 to 45 seconds.Withdrawfrom thevial into a syringe.Label the syringe with the dose strength (0.16 mg) and the time of day.

Discard the vial containing unused EPKINLY.

0.8 mg Dose Preparation Instructions (

1 dilution required

) – Empty Sterile Vial Method

Use an appropriately sized syringe, vial, and needle for each transfer step.

*
*

DO NOT

Dilution A

0.8 mL of EPKINLY

Dilution A

4.2 mL of 0.9% Sodium Chloride Injection

Dilution A

1 mL of the diluted EPKINLY

Dilution A

a.
1. Prepare EPKINLY vial *
2. Perform dilution *
3. Withdraw dose *
4. Label syringe *

Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.Allow the vial to come to room temperature for no more than 1 hour.Gently swirl the EPKINLY vial.invert, vortex, or vigorously shake the vial.Label an appropriately sized empty vial as "".Transferinto thevial.Transferinto thevial to make a final concentration of 0.8 mg/mL.Gently swirl thevial for 30 to 45 seconds.Withdrawfrom thevial into a syringe.Label the syringe with the dose strength (0.8 mg) and the time of day.

Discard the vial containing unused EPKINLY.

2.8 Preparation of Diluted EPKINLY using the Syringe Method

Read this entire section carefully before preparation of EPKINLY. Certain doses of EPKINLY require

dilution

prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to improper dose.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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

0.16 mg Dose Preparation Instructions (

2 dilutions required

) – Sterile Syringe Method

Use an appropriately sized syringe and needle for each transfer step.

*
*

DO NOT

"Dilution A."

4.2 mL of 0.9% Sodium Chloride Injection

Dilution A

"Syringe 1"

0.8 mL of EPKINLY

Dilution A

*
*

Syringe 1

"Dilution B."

8 mL of 0.9% Sodium Chloride Injection

Dilution B

"Syringe 2."

Syringe 2

Dilution A

2 mL of solution

Syringe 2

Dilution A

Syringe 2

Dilution B

2 mL of solution

Dilution B

*
*

Syringe 2

1 mL of the diluted EPKINLY

Dilution B

a.
1. Prepare EPKINLY vial *
2. Perform first dilution *
3. Perform second dilution *
4. Withdraw dose *
5. Label syringe *

Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.Allow the vial to come to room temperature for no more than 1 hour.Gently swirl the EPKINLY vial.invert, vortex, or vigorously shake the vial.Label an appropriately sized syringe asWithdrawinto thesyringe. Include approximately 0.2 mL air in the syringe.In a new syringe labeled as, withdraw.Connect the two syringes and push theinto thesyringe. The initially diluted solution contains 0.8 mg/mL of EPKINLYGently mix by inverting the connected syringes 180 degrees 5 times.Disconnect the syringes and discard.Label an appropriately sized syringe asWithdrawinto thesyringe. Include approximately 0.2 mL air in the syringe.Label another appropriately sized syringe asConnectto thesyringe and transferinto. Thesyringe is no longer needed.Connectto thesyringe and push theinto thesyringe to make a final concentration of 0.16 mg/mL.Gently mix by inverting the connected syringes 180 degrees 5 times.Disconnect the syringes and discard.Connect and transferfrom thesyringe into a new syringe. Thesyringe is no longer neededLabel the syringe with the dose strength (0.16 mg) and the time of day.

Discard the vial containing unused EPKINLY.

0.8 mg Dose Preparation Instructions (

1 dilution required

) – Sterile Syringe Method

Use an appropriately sized syringe and needle for each transfer step.

*
*

DO NOT

"Dilution A."

4.2 mL of 0.9% Sodium Chloride Injection

Dilution A

Syringe 1

0.8 mL of EPKINLY

Dilution A

*
*

Syringe 1

Dilution A

1 mL of the diluted EPKINLY

Dilution A

a.
1. Prepare EPKINLY vial *
2. Perform dilution *
3. Withdraw dose *
4. Label syringe *

Discard the vial containing unused EPKINLY.

)
* See Full Prescribing Information for instructions on preparation and administration. (

2.7 Preparation of Diluted EPKINLY using the Vial Method

Read this entire section carefully before preparation of EPKINLY. Certain doses of EPKINLY require

dilution

[see Dosage and Administration (2.8)]

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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

0.16 mg Dose Preparation Instructions (

2 dilutions required

) – Empty Sterile Vial Method

Use an appropriately sized syringe, vial, and needle for each transfer step.

*
*

DO NOT

"Dilution A."

0.8 mL of EPKINLY

Dilution A

4.2 mL of 0.9% Sodium Chloride Injection

Dilution A

"Dilution B."

2 mL of solution

Dilution A

Dilution B

Dilution A

8 mL of 0.9% Sodium Chloride Injection

Dilution B

1 mL of the diluted EPKINLY

Dilution B

a.
1. Prepare EPKINLY vial *
2. Perform first dilution *
3. Perform second dilution *
4. Withdraw dose *
5. Label syringe *

Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.Allow the vial to come to room temperature for no more than 1 hour.Gently swirl the EPKINLY vial.invert, vortex, or vigorously shake the vial.Label an appropriately sized empty vial asTransferinto thevial.Transferinto thevial.The initially diluted solution contains 0.8 mg/mL of EPKINLY.Gently swirl thevial for 30 to 45 seconds.Label an appropriately sized empty vial asTransferfrom thevial into thevial. Thevial is no longer needed.Transferinto thevial to make a final concentration of 0.16 mg/mL.Gently swirl thevial for 30 to 45 seconds.Withdrawfrom thevial into a syringe.Label the syringe with the dose strength (0.16 mg) and the time of day.

Discard the vial containing unused EPKINLY.

0.8 mg Dose Preparation Instructions (

1 dilution required

) – Empty Sterile Vial Method

Use an appropriately sized syringe, vial, and needle for each transfer step.

*
*

DO NOT

Dilution A

0.8 mL of EPKINLY

Dilution A

4.2 mL of 0.9% Sodium Chloride Injection

Dilution A

1 mL of the diluted EPKINLY

Dilution A

a.
1. Prepare EPKINLY vial *
2. Perform dilution *
3. Withdraw dose *
4. Label syringe *

Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.Allow the vial to come to room temperature for no more than 1 hour.Gently swirl the EPKINLY vial.invert, vortex, or vigorously shake the vial.Label an appropriately sized empty vial as "".Transferinto thevial.Transferinto thevial to make a final concentration of 0.8 mg/mL.Gently swirl thevial for 30 to 45 seconds.Withdrawfrom thevial into a syringe.Label the syringe with the dose strength (0.8 mg) and the time of day.

Discard the vial containing unused EPKINLY.

2.8 Preparation of Diluted EPKINLY using the Syringe Method

Read this entire section carefully before preparation of EPKINLY. Certain doses of EPKINLY require

dilution

prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to improper dose.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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

0.16 mg Dose Preparation Instructions (

2 dilutions required

) – Sterile Syringe Method

Use an appropriately sized syringe and needle for each transfer step.

*
*

DO NOT

"Dilution A."

4.2 mL of 0.9% Sodium Chloride Injection

Dilution A

"Syringe 1"

0.8 mL of EPKINLY

Dilution A

*
*

Syringe 1

"Dilution B."

8 mL of 0.9% Sodium Chloride Injection

Dilution B

"Syringe 2."

Syringe 2

Dilution A

2 mL of solution

Syringe 2

Dilution A

Syringe 2

Dilution B

2 mL of solution

Dilution B

*
*

Syringe 2

1 mL of the diluted EPKINLY

Dilution B

a.
1. Prepare EPKINLY vial *
2. Perform first dilution *
3. Perform second dilution *
4. Withdraw dose *
5. Label syringe *

Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.Allow the vial to come to room temperature for no more than 1 hour.Gently swirl the EPKINLY vial.invert, vortex, or vigorously shake the vial.Label an appropriately sized syringe asWithdrawinto thesyringe. Include approximately 0.2 mL air in the syringe.In a new syringe labeled as, withdraw.Connect the two syringes and push theinto thesyringe. The initially diluted solution contains 0.8 mg/mL of EPKINLYGently mix by inverting the connected syringes 180 degrees 5 times.Disconnect the syringes and discard.Label an appropriately sized syringe asWithdrawinto thesyringe. Include approximately 0.2 mL air in the syringe.Label another appropriately sized syringe asConnectto thesyringe and transferinto. Thesyringe is no longer needed.Connectto thesyringe and push theinto thesyringe to make a final concentration of 0.16 mg/mL.Gently mix by inverting the connected syringes 180 degrees 5 times.Disconnect the syringes and discard.Connect and transferfrom thesyringe into a new syringe. Thesyringe is no longer neededLabel the syringe with the dose strength (0.16 mg) and the time of day.

Discard the vial containing unused EPKINLY.

0.8 mg Dose Preparation Instructions (

1 dilution required

) – Sterile Syringe Method

Use an appropriately sized syringe and needle for each transfer step.

*
*

DO NOT

"Dilution A."

4.2 mL of 0.9% Sodium Chloride Injection

Dilution A

Syringe 1

0.8 mL of EPKINLY

Dilution A

*
*

Syringe 1

Dilution A

1 mL of the diluted EPKINLY

Dilution A

a.
1. Prepare EPKINLY vial *
2. Perform dilution *
3. Withdraw dose *
4. Label syringe *

Discard the vial containing unused EPKINLY.

2.9 Preparation of 3 mg and 48 mg EPKINLY Doses

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Use aseptic technique to prepare EPKINLY.

3 mg Dose Preparation Instructions

(No dilution required)

EPKINLY 3 mg dose is required for patients with FL only

[see Dosage and Administration (2.2)]

*
*

0.6 mL of EPKINLY

a.
1. Prepare EPKINLY vial *
DO NOT invert, vortex, or vigorously shake the vial.
2. Withdraw dose *
3. Label syringe *

Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.Allow the vial to come to room temperature for no more than 1 hour.Gently swirl the EPKINLY vial.Withdrawinto a syringe.Label the syringe with the dose strength (3 mg) and the time of day.

Discard the vial containing unused EPKINLY.

48 mg Dose Preparation Instructions (

No dilution required

)

EPKINLY 48 mg/0.8 mL vial is supplied as ready-to-use solution that does not need dilution prior to administration.

*
*

0.8 mL of EPKINLY

a.
1. Prepare EPKINLY vial *
DO NOT invert, vortex, or vigorously shake the vial.
2. Withdraw dose *
3. Label syringe *

Retrieve one 48 mg/0.8 mL EPKINLY vial from the refrigerator.Allow the vial to come to room temperature for no more than 1 hour.Gently swirl the EPKINLY vial.Withdrawinto a syringe.Label the syringe with the dose strength (48 mg) and the time of day.

Discard the vial containing unused EPKINLY.

2.10 Storage and Administration

Storage of EPKINLY Solution in the Syringe

Use EPKINLY solution in the syringe immediately. If not used immediately, store the solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at room temperature at 20°C to 25°C (68°F to 77°F) for up to 12 hours. The total storage time from the start of dose preparation to administration should not exceed 24 hours. Protect from direct sunlight. Discard unused EPKINLY solution beyond the allowable storage time.

Administration of EPKINLY

To minimize injection pain, allow EPKINLY solution to equilibrate to room temperature for no more than 1 hour before administration. Inject the required volume of EPKINLY into the subcutaneous tissue of the lower part of the abdomen (preferred injection site) or the thigh.

Change of injection site from the left or right side or vice versa is recommended, especially during the weekly administrations (Cycles 1 to 3). Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, or not intact.

)

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Epkinly Prescribing Information

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

[see

2.1 Important Dosing Information

Certain doses of EPKINLY require
dilution
prior to administration. There are 2 available methods to prepare
diluted
EPKINLY:
- Empty sterile vial method as described in subsection 2.7
  [see Dosage and Administration (2.7)]
  , or
- Sterile syringe method as described in subsection 2.8
  [see Dosage and Administration (2.8)]
  .
Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution.
[see Dosage and Administration (2.9)]
.
EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS
[see Warnings and Precautions (5.1, 5.2)]
.
Administer EPKINLY to well-hydrated patients.
Premedicate before each dose in Cycle 1
[see Dosage and Administration (2.4)]
.
Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS
[see Dosage and Administration (2.2)]
.
Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms
[see Dosage and Administration (2.6)]
.
- For patients with DLBCL or high-grade B-cell lymphoma:
  
  Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg
  [see Dosage and Administration (2.2)].
- For patients with FL:
  
  Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the Cycle 1 Day 22 dosage of 48 mg
  [see Dosage and Administration (2.2)
  ].

2.2 Recommended Dosage

EPKINLY is for subcutaneous injection only.

The recommended DLBCL dosage for Cycle 1 consists of 2 step-up doses, and the recommended FL dosage (monotherapy or in combination with lenalidomide and rituximab) consists of 3 step-up doses.

EPKINLY as Monotherapy:

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

Table 1: EPKINLY Dosage Schedule for Patients with DLBCL or High-grade B-cell Lymphoma
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
DLBCL or High-grade B-cell Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	First full dose	48 mg
		22	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

Table 2: EPKINLY Dosage Schedule for Patients with FL when Given as Monotherapy
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

EPKINLY in Combination with Lenalidomide and Rituximab:

Administer EPKINLY in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurs first.

Table 3: EPKINLY Dosage Schedule in Combination with Lenalidomide and Rituximab for Patients with FL
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15, and 22	48 mg
	Cycles 4 to 12	1	48 mg

Administer EPKINLY in combination with lenalidomide 20 mg (Days 1 to 21 in Cycles 1 to 12) and rituximab 375 mg/m²(Cycles 1 to 5)

[see Clinical Studies (14.2)].

2.6 Dosage Modifications and Management of Adverse Reactions

See Tables 7and 8for recommended actions for adverse reactions of CRS and ICANS, respectively. See Tables 9and 10for recommended actions for other adverse reactions following administration of EPKINLY given as monotherapy and in combination with lenalidomide and rituximab, respectively.

Cytokine Release Syndrome (CRS)

Identify CRS based on clinical presentation

[see Warnings and Precautions (5.1)]

. Evaluate for and treat other causes of fever, hypotension, and hypoxia.

If CRS is suspected, withhold EPKINLY until CRS resolves. Manage according to the recommendations in Table 7 and consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS.

Table 7: Recommendations for Management of Cytokine Release Syndrome
GradeBased on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS.	Presenting Symptoms	Actions
Grade 1	Temperature ≥ 100.4°F (38°C)Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow these management guidelines.	Withhold EPKINLY and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of EPKINLY.Refer to Table 4 or Table 5 for information on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)] .
Grade 2	Temperature ≥ 100.4°F (38°C) with: Hypotension not requiring vasopressors and/or Hypoxia requiring low-flow oxygenLow-flow oxygen defined as oxygen delivered at < 6L/minute; high-flow oxygen defined as oxygen delivered at ≥ 6 L/minute.by nasal cannula or blow-by.	Withhold EPKINLY and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of EPKINLY. Administer premedicationIf Grade 2 or 3 CRS occurs with the second full dose (48 mg) or beyond, administer CRS pre- and post-administration medications with each subsequent dose until a EPKINLY dose is given without subsequent CRS of Grade 2 or higher. Refer to Table 6 for additional information on pre- and post-administration medications.prior to next dose of EPKINLY. For the next dose of EPKINLY, monitor more frequently and consider hospitalization.
Grade 3	Temperature ≥ 100.4°F (38°C) with: Hypotension requiring a vasopressor (with or without vasopressin) and/or Hypoxia requiring high-flow oxygen by nasal cannula, face mask, non-rebreather mask, or Venturi mask.	Withhold EPKINLY and manage per current practice guidelines, which may include intensive care. Ensure CRS symptoms are resolved prior to the next dose of EPKINLY. Administer premedication prior to next dose of EPKINLY. Hospitalize for the next dose of EPKINLY.
Grade 3		Recurrent Grade 3 CRS Permanently discontinue EPKINLY. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care.
Grade 4	Temperature ≥ 100.4°F (38°C) with: Hypotension requiring multiple vasopressors (excluding vasopressin) and/or Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation).	Permanently discontinue EPKINLY. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care.

Immune Effector Cell-Associated Neurological Toxicity Syndrome (ICANS)

Monitor patients for signs and symptoms of ICANS

[see Warnings and Precautions (5.2)]

. At the first sign of ICANS, withhold EPKINLY and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for ICANS

[see Warnings and Precautions (5.2)].

Manage ICANS according to the recommendations in Table 8 and consider further management per current practice guidelines.

Table 8: Recommendations for Management of Immune Effector Cell-Associated Neurotoxicity Syndrome
GradeBased on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS.	Presenting SymptomsManagement is determined by the most severe event, not attributable to any other cause.	Actions
Grade 1	ICE score 7-9If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (names 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., "show me 2 fingers" or "close your eyes and stick out your tongue" = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points., Or depressed level of consciousnessNot attributable to any other cause.: awakens spontaneously.	Withhold EPKINLY until ICANS resolves.See Table 4or Table 5for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)]. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis.
Grade 2	ICE score 3-6 , Or depressed level of consciousness : awakens to voice.	Withhold EPKINLY until ICANS resolves. Administer dexamethasoneAll references to dexamethasone administration are dexamethasone or equivalent.10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis.
Grade 3	ICE score 0-2 , Or depressed level of consciousness : awakens only to tactile stimulus, Or seizures, either: Any clinical seizure, focal or generalized, that resolves rapidly, or Non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, Or raised intracranial pressure: focal/local edema on neuroimaging.	First Occurrence of Grade 3 ICANS Withhold EPKINLY until ICANS resolves. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care.
Grade 3		Recurrent Grade 3 ICANS Permanently discontinue EPKINLY Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care.
Grade 4	ICE score 0 , Or depressed level of consciousness : either: Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or Stupor or coma Or seizures, either: Life-threatening prolonged seizure (> 5 minutes), or Repetitive clinical or electrical seizures without return to baseline in between, Or motor findings : Deep focal motor weakness, such as hemiparesis or paraparesis, or raised intracranial pressure/cerebral edema, with signs/symptoms such as: Diffuse cerebral edema on neuroimaging, or Decerebrate or decorticate posturing, or Cranial nerve VI palsy, or Papilledema, or Cushing's triad.	Permanently discontinue EPKINLY. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Alternatively, consider administration of methylprednisolone 1,000 mg per day intravenously and continue methylprednisolone 1,000 mg per day intravenously for 2 or more days. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care.

Table 9: Recommended Dosage Modifications for Other Adverse Reactions when EPKINLY is Given as Monotherapy
Adverse ReactionBased on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.	Severity	Action
Infections [see Warnings and Precautions (5.3)]	Grades 1-4	Withhold EPKINLY in patients with active infection, until the infection resolves.See Table 4or Table 5for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)]. For Grade 4, consider permanent discontinuation of EPKINLY.
Neutropenia [see Warnings and Precautions (5.4)]	Absolute neutrophil count less than 0.5 × 10⁹/L	Withhold EPKINLY until absolute neutrophil count is 0.5 × 10⁹/L or higher.
Thrombocytopenia [see Warnings and Precautions (5.4)]	Platelet count less than 50 × 10⁹/L	Withhold EPKINLY until platelet count is 50 × 10⁹/L or higher.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3 or higher	Withhold EPKINLY until the toxicity resolves to Grade 1 or baseline.

Table 10: Recommended Dosage Modifications for Other Adverse Reactions when EPKINLY is Given in Combination with Lenalidomide and Rituximab
Adverse Reaction	SeverityBased on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.	ActionRefer to lenalidomide prescribing information for additional toxicity guidelines.
Neutropenia [see Warnings and Precautions (5.4)]	Absolute neutrophil count less than 0.5 × 10⁹/L	Consider G-CSF. Withhold EPKINLY until absolute neutrophil count is 1 × 10⁹/L or higher.See Table 4or 5for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)]. Withhold lenalidomide for remainder of cycle. On Day 1 of next cycle, the dose of lenalidomide may be maintained if neutropenia was the only toxicity limiting lenalidomide dosing.
Febrile Neutropenia [see Warnings and Precautions (5.4)]	Grade 3 or higher	Consider G-CSF. Withhold EPKINLY until fever resolves and absolute neutrophil count is 1 × 10⁹/L or higher. Withhold lenalidomide for remainder of cycle. On Day 1 of next cycle, dose of lenalidomide may be maintained if febrile neutropenia was the only toxicity limiting lenalidomide dosing.
Thrombocytopenia [see Warnings and Precautions (5.4)]	Platelet count less than 50 × 10⁹/L	Withhold EPKINLY until platelet count is 50 × 10⁹/L or higher. Withhold lenalidomide for remainder of cycle. Decrease lenalidomide dose for next cycle.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3	For first episode, withhold EPKINLY until improvement to Grade 2 or less or resolution to baseline. For second episode, permanently discontinue EPKINLY if clinically indicated.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 4	Permanently discontinue EPKINLY at discretion of healthcare provider.

and

5.1 Cytokine Release Syndrome

EPKINLY can cause CRS, including serious or fatal reactions

[see Adverse Reactions (6.1)]

Relapsed or Refractory Large B-cell Lymphoma

CRS occurred in 51% (80/157) of patients with LBCL receiving EPKINLY at the recommended dosage schedule in EPCORE NHL-1, with Grade 1 CRS occurring in 37%, Grade 2 in 17%, and Grade 3 in 2.5% of patients. Recurrent CRS occurred in 31% of these patients. Most CRS events (92%) occurred during Cycle 1. In Cycle 1, CRS events occurred in 6% of patients after the 0.16 mg dose, 12% after the 0.8 mg dose, 43% after the first 48 mg dose, and 5% after the next 48 mg dose. The median time to onset of CRS from the most recent EPKINLY dose was 24 hours (range: 0 to 10 days). The median time to onset after the first 48 mg dose was 21 hours (range: 0 to 7 days).

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

[see Dosage and Administration (2.1, 2.2)].

Relapsed or Refractory Follicular Lymphoma

CRS occurred in 49% (42/86) of patients with FL receiving EPKINLY monotherapy at the recommended dosage schedule in EPCORE NHL-1, with Grade 1 CRS occurring in 45% and Grade 2 in 9% of patients. Recurrent CRS occurred in 48% of patients. Most CRS events (88%) occurred during Cycle 1. In Cycle 1, CRS events occurred in 12% of patients after the 0.16 mg dose, 6% after the 0.8 mg dose, 15% after the 3 mg dose, and 37% after the first 48 mg dose. The median time to onset of CRS from the most recent EPKINLY dose was 59 hours (range: 0.1 to 7 days). The median time to onset after the first 48 mg dose was 61 hours (range: 0.1 to 7 days).

CRS occurred in 24% (32/131) of patients with FL receiving EPKINLY at the recommended dosage schedule in combination with lenalidomide and rituximab in EPCORE FL-1, with Grade 1 CRS occurring in 19%, Grade 2 in 5% of patients, and serious adverse reactions due to CRS in 12%. Recurrent CRS occurred in 41% of patients. Most CRS events (88%) occurred during Cycle 1. In Cycle 1, CRS occurred in 5% of patients after the 0.16 mg dose, 3.8% after the 0.8 mg dose, 2.3% after the 3 mg dose, and 18% after the first 48 mg dose. The median time to onset of CRS from the most recent EPKINLY dose was 78 hours (range: 0.2 to 12 days). The median time to onset after the first 48 mg dose was 41 hours (range: 0.3 to 12 days).

For patients with FL, assess whether hospitalization or outpatient monitoring for the first 48 mg dose is appropriate based on comorbidities or other situational factors

[see Dosage and Administration (2.1)]

. During outpatient monitoring after the first 48 mg dose, patients should remain in proximity to a healthcare facility that can assess and manage CRS.

Among patients with LBCL or FL who experienced CRS, signs and symptoms included pyrexia, hypotension, hypoxia, dyspnea, chills, and tachycardia. CRS resolved in 98% of patients, after a median duration of 2 days (range: < 1 to 27 days). Concurrent neurological adverse reactions associated with CRS occurred in 2.5% of patients with LBCL, 4.7% of patients with FL receiving EPKINLY monotherapy, and 1.5% of patients receiving EPKINLY in combination with lenalidomide and rituximab. Concurrent neurological adverse reactions included headache, confusional state, tremors, dizziness, and ataxia.

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

[see Dosage and Administration (2.2, 2.3, 2.4)]

. At the first signs or symptoms of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care as appropriate. Withhold or discontinue EPKINLY based on the severity of CRS

[see Dosage and Administration (2.6)]

Patients who experience CRS (or other adverse reactions that impair consciousness) should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.

]

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

[see

2.1 Important Dosing Information

Certain doses of EPKINLY require
dilution
prior to administration. There are 2 available methods to prepare
diluted
EPKINLY:
- Empty sterile vial method as described in subsection 2.7
  [see Dosage and Administration (2.7)]
  , or
- Sterile syringe method as described in subsection 2.8
  [see Dosage and Administration (2.8)]
  .
Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution.
[see Dosage and Administration (2.9)]
.
EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS
[see Warnings and Precautions (5.1, 5.2)]
.
Administer EPKINLY to well-hydrated patients.
Premedicate before each dose in Cycle 1
[see Dosage and Administration (2.4)]
.
Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS
[see Dosage and Administration (2.2)]
.
Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms
[see Dosage and Administration (2.6)]
.
- For patients with DLBCL or high-grade B-cell lymphoma:
  
  Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg
  [see Dosage and Administration (2.2)].
- For patients with FL:
  
  Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the Cycle 1 Day 22 dosage of 48 mg
  [see Dosage and Administration (2.2)
  ].

2.2 Recommended Dosage

EPKINLY is for subcutaneous injection only.

The recommended DLBCL dosage for Cycle 1 consists of 2 step-up doses, and the recommended FL dosage (monotherapy or in combination with lenalidomide and rituximab) consists of 3 step-up doses.

EPKINLY as Monotherapy:

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

Table 1: EPKINLY Dosage Schedule for Patients with DLBCL or High-grade B-cell Lymphoma
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
DLBCL or High-grade B-cell Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	First full dose	48 mg
		22	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

Table 2: EPKINLY Dosage Schedule for Patients with FL when Given as Monotherapy
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

EPKINLY in Combination with Lenalidomide and Rituximab:

Administer EPKINLY in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurs first.

Table 3: EPKINLY Dosage Schedule in Combination with Lenalidomide and Rituximab for Patients with FL
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15, and 22	48 mg
	Cycles 4 to 12	1	48 mg

Administer EPKINLY in combination with lenalidomide 20 mg (Days 1 to 21 in Cycles 1 to 12) and rituximab 375 mg/m²(Cycles 1 to 5)

[see Clinical Studies (14.2)].

2.6 Dosage Modifications and Management of Adverse Reactions

Cytokine Release Syndrome (CRS)

Identify CRS based on clinical presentation

[see Warnings and Precautions (5.1)]

. Evaluate for and treat other causes of fever, hypotension, and hypoxia.

Table 7: Recommendations for Management of Cytokine Release Syndrome
GradeBased on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS.	Presenting Symptoms	Actions
Grade 1	Temperature ≥ 100.4°F (38°C)Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow these management guidelines.	Withhold EPKINLY and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of EPKINLY.Refer to Table 4 or Table 5 for information on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)] .
Grade 2	Temperature ≥ 100.4°F (38°C) with: Hypotension not requiring vasopressors and/or Hypoxia requiring low-flow oxygenLow-flow oxygen defined as oxygen delivered at < 6L/minute; high-flow oxygen defined as oxygen delivered at ≥ 6 L/minute.by nasal cannula or blow-by.	Withhold EPKINLY and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of EPKINLY. Administer premedicationIf Grade 2 or 3 CRS occurs with the second full dose (48 mg) or beyond, administer CRS pre- and post-administration medications with each subsequent dose until a EPKINLY dose is given without subsequent CRS of Grade 2 or higher. Refer to Table 6 for additional information on pre- and post-administration medications.prior to next dose of EPKINLY. For the next dose of EPKINLY, monitor more frequently and consider hospitalization.
Grade 3	Temperature ≥ 100.4°F (38°C) with: Hypotension requiring a vasopressor (with or without vasopressin) and/or Hypoxia requiring high-flow oxygen by nasal cannula, face mask, non-rebreather mask, or Venturi mask.	Withhold EPKINLY and manage per current practice guidelines, which may include intensive care. Ensure CRS symptoms are resolved prior to the next dose of EPKINLY. Administer premedication prior to next dose of EPKINLY. Hospitalize for the next dose of EPKINLY.
Grade 3		Recurrent Grade 3 CRS Permanently discontinue EPKINLY. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care.
Grade 4	Temperature ≥ 100.4°F (38°C) with: Hypotension requiring multiple vasopressors (excluding vasopressin) and/or Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation).	Permanently discontinue EPKINLY. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care.

Immune Effector Cell-Associated Neurological Toxicity Syndrome (ICANS)

Monitor patients for signs and symptoms of ICANS

[see Warnings and Precautions (5.2)]

. At the first sign of ICANS, withhold EPKINLY and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for ICANS

[see Warnings and Precautions (5.2)].

Manage ICANS according to the recommendations in Table 8 and consider further management per current practice guidelines.

Table 8: Recommendations for Management of Immune Effector Cell-Associated Neurotoxicity Syndrome
GradeBased on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS.	Presenting SymptomsManagement is determined by the most severe event, not attributable to any other cause.	Actions
Grade 1	ICE score 7-9If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (names 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., "show me 2 fingers" or "close your eyes and stick out your tongue" = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points., Or depressed level of consciousnessNot attributable to any other cause.: awakens spontaneously.	Withhold EPKINLY until ICANS resolves.See Table 4or Table 5for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)]. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis.
Grade 2	ICE score 3-6 , Or depressed level of consciousness : awakens to voice.	Withhold EPKINLY until ICANS resolves. Administer dexamethasoneAll references to dexamethasone administration are dexamethasone or equivalent.10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis.
Grade 3	ICE score 0-2 , Or depressed level of consciousness : awakens only to tactile stimulus, Or seizures, either: Any clinical seizure, focal or generalized, that resolves rapidly, or Non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, Or raised intracranial pressure: focal/local edema on neuroimaging.	First Occurrence of Grade 3 ICANS Withhold EPKINLY until ICANS resolves. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care.
Grade 3		Recurrent Grade 3 ICANS Permanently discontinue EPKINLY Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care.
Grade 4	ICE score 0 , Or depressed level of consciousness : either: Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or Stupor or coma Or seizures, either: Life-threatening prolonged seizure (> 5 minutes), or Repetitive clinical or electrical seizures without return to baseline in between, Or motor findings : Deep focal motor weakness, such as hemiparesis or paraparesis, or raised intracranial pressure/cerebral edema, with signs/symptoms such as: Diffuse cerebral edema on neuroimaging, or Decerebrate or decorticate posturing, or Cranial nerve VI palsy, or Papilledema, or Cushing's triad.	Permanently discontinue EPKINLY. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Alternatively, consider administration of methylprednisolone 1,000 mg per day intravenously and continue methylprednisolone 1,000 mg per day intravenously for 2 or more days. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care.

Table 9: Recommended Dosage Modifications for Other Adverse Reactions when EPKINLY is Given as Monotherapy
Adverse ReactionBased on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.	Severity	Action
Infections [see Warnings and Precautions (5.3)]	Grades 1-4	Withhold EPKINLY in patients with active infection, until the infection resolves.See Table 4or Table 5for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)]. For Grade 4, consider permanent discontinuation of EPKINLY.
Neutropenia [see Warnings and Precautions (5.4)]	Absolute neutrophil count less than 0.5 × 10⁹/L	Withhold EPKINLY until absolute neutrophil count is 0.5 × 10⁹/L or higher.
Thrombocytopenia [see Warnings and Precautions (5.4)]	Platelet count less than 50 × 10⁹/L	Withhold EPKINLY until platelet count is 50 × 10⁹/L or higher.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3 or higher	Withhold EPKINLY until the toxicity resolves to Grade 1 or baseline.

Table 10: Recommended Dosage Modifications for Other Adverse Reactions when EPKINLY is Given in Combination with Lenalidomide and Rituximab
Adverse Reaction	SeverityBased on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.	ActionRefer to lenalidomide prescribing information for additional toxicity guidelines.
Neutropenia [see Warnings and Precautions (5.4)]	Absolute neutrophil count less than 0.5 × 10⁹/L	Consider G-CSF. Withhold EPKINLY until absolute neutrophil count is 1 × 10⁹/L or higher.See Table 4or 5for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)]. Withhold lenalidomide for remainder of cycle. On Day 1 of next cycle, the dose of lenalidomide may be maintained if neutropenia was the only toxicity limiting lenalidomide dosing.
Febrile Neutropenia [see Warnings and Precautions (5.4)]	Grade 3 or higher	Consider G-CSF. Withhold EPKINLY until fever resolves and absolute neutrophil count is 1 × 10⁹/L or higher. Withhold lenalidomide for remainder of cycle. On Day 1 of next cycle, dose of lenalidomide may be maintained if febrile neutropenia was the only toxicity limiting lenalidomide dosing.
Thrombocytopenia [see Warnings and Precautions (5.4)]	Platelet count less than 50 × 10⁹/L	Withhold EPKINLY until platelet count is 50 × 10⁹/L or higher. Withhold lenalidomide for remainder of cycle. Decrease lenalidomide dose for next cycle.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3	For first episode, withhold EPKINLY until improvement to Grade 2 or less or resolution to baseline. For second episode, permanently discontinue EPKINLY if clinically indicated.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 4	Permanently discontinue EPKINLY at discretion of healthcare provider.

and

5.2 Immune Effector Cell-Associated Neurotoxicity Syndrome

EPKINLY can cause life-threatening and fatal immune effector cell-associated neurotoxicity syndrome (ICANS)

[see Adverse Reactions (6.1)]

Relapsed or Refractory Large B-cell Lymphoma

ICANS occurred in 6% (10/157) of patients with LBCL receiving EPKINLY at the recommended dosage schedule in EPCORE NHL-1, with Grade 1 ICANS in 4.5% and Grade 2 ICANS in 1.3% of patients. There was one (0.6%) fatal ICANS occurrence. Of the 10 ICANS events, 9 occurred within Cycle 1 of EPKINLY treatment, with a median time to onset of ICANS of 16.5 days (range: 8 to 141 days) from the start of treatment. Relative to the most recent administration of EPKINLY, the median time to onset of ICANS was 3 days (range: 1 to 13 days). The median duration of ICANS was 4 days (range: 0 to 8 days) with ICANS resolving in 90% of patients with supportive care.

Relapsed or Refractory Follicular Lymphoma

ICANS occurred in 6% (8/127) of patients with FL receiving EPKINLY monotherapy following the 2-step up dosage schedule in EPCORE NHL-1, with Grade 1 ICANS in 3.9% and Grade 2 ICANS in 2.4% of patients. The median time to onset of ICANS was 22 days (range: 14 to 66 days) from the start of treatment. Relative to the most recent administration of EPKINLY, the median time to onset of ICANS was 3 days (range: 0.4 to 7 days). The median duration of ICANS was 2 days (range: 1 to 7 days) with ICANS resolving in 100% of patients.

Among patients with FL who received EPINKLY at the recommended dosage schedule in combination with lenalidomide and rituximab in EPCORE FL-1, ICANS occurred in 0.8% (1/131, Grade 1).

For patients with LBCL or FL, clinical manifestations of ICANS included, but were not limited to confusional state, lethargy, tremor, dysgraphia, aphasia, and non-convulsive status epilepticus. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Monitor patients for potential ICANS following EPKINLY. At the first signs or symptoms of ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or discontinue EPKINLY per recommendations and consider further management per current practice guidelines

[see Dosage and Administration (2.6)]

Patients who experience signs or symptoms of ICANS or any other adverse reactions that impair cognition or consciousness should be evaluated, including potential neurology evaluation, and patients at increased risk should be advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.

]

Indications and Usage (

1.2 Follicular Lymphoma

EPKINLY is indicated in combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL).

EPKINLY is indicated as monotherapy for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.

)

11/2025

Dosage and Administration (

2.1 Important Dosing Information

Certain doses of EPKINLY require
dilution
prior to administration. There are 2 available methods to prepare
diluted
EPKINLY:
- Empty sterile vial method as described in subsection 2.7
  [see Dosage and Administration (2.7)]
  , or
- Sterile syringe method as described in subsection 2.8
  [see Dosage and Administration (2.8)]
  .
Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution.
[see Dosage and Administration (2.9)]
.
EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS
[see Warnings and Precautions (5.1, 5.2)]
.
Administer EPKINLY to well-hydrated patients.
Premedicate before each dose in Cycle 1
[see Dosage and Administration (2.4)]
.
Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS
[see Dosage and Administration (2.2)]
.
Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms
[see Dosage and Administration (2.6)]
.
- For patients with DLBCL or high-grade B-cell lymphoma:
  
  Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg
  [see Dosage and Administration (2.2)].
- For patients with FL:
  
  Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the Cycle 1 Day 22 dosage of 48 mg
  [see Dosage and Administration (2.2)
  ].

2.2 Recommended Dosage

EPKINLY is for subcutaneous injection only.

The recommended DLBCL dosage for Cycle 1 consists of 2 step-up doses, and the recommended FL dosage (monotherapy or in combination with lenalidomide and rituximab) consists of 3 step-up doses.

EPKINLY as Monotherapy:

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

Table 1: EPKINLY Dosage Schedule for Patients with DLBCL or High-grade B-cell Lymphoma
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
DLBCL or High-grade B-cell Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	First full dose	48 mg
		22	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

Table 2: EPKINLY Dosage Schedule for Patients with FL when Given as Monotherapy
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

EPKINLY in Combination with Lenalidomide and Rituximab:

Administer EPKINLY in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurs first.

Table 3: EPKINLY Dosage Schedule in Combination with Lenalidomide and Rituximab for Patients with FL
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15, and 22	48 mg
	Cycles 4 to 12	1	48 mg

Administer EPKINLY in combination with lenalidomide 20 mg (Days 1 to 21 in Cycles 1 to 12) and rituximab 375 mg/m²(Cycles 1 to 5)

[see Clinical Studies (14.2)].

2.5 Recommended Prophylaxis

Pneumocystis jirovecii pneumonia (PJP)

Provide PJP prophylaxis during treatment with EPKINLY.

Herpesvirus

Consider providing prophylaxis against herpesvirus during treatment with EPKINLY to prevent herpes simplex and herpes zoster.

Thromboprophylaxis

Refer to the lenalidomide prescribing information for recommendations on prophylaxis for venous and arterial thrombotic events.

2.6 Dosage Modifications and Management of Adverse Reactions

Cytokine Release Syndrome (CRS)

Identify CRS based on clinical presentation

[see Warnings and Precautions (5.1)]

. Evaluate for and treat other causes of fever, hypotension, and hypoxia.

Table 7: Recommendations for Management of Cytokine Release Syndrome
GradeBased on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS.	Presenting Symptoms	Actions
Grade 1	Temperature ≥ 100.4°F (38°C)Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow these management guidelines.	Withhold EPKINLY and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of EPKINLY.Refer to Table 4 or Table 5 for information on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)] .
Grade 2	Temperature ≥ 100.4°F (38°C) with: Hypotension not requiring vasopressors and/or Hypoxia requiring low-flow oxygenLow-flow oxygen defined as oxygen delivered at < 6L/minute; high-flow oxygen defined as oxygen delivered at ≥ 6 L/minute.by nasal cannula or blow-by.	Withhold EPKINLY and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of EPKINLY. Administer premedicationIf Grade 2 or 3 CRS occurs with the second full dose (48 mg) or beyond, administer CRS pre- and post-administration medications with each subsequent dose until a EPKINLY dose is given without subsequent CRS of Grade 2 or higher. Refer to Table 6 for additional information on pre- and post-administration medications.prior to next dose of EPKINLY. For the next dose of EPKINLY, monitor more frequently and consider hospitalization.
Grade 3	Temperature ≥ 100.4°F (38°C) with: Hypotension requiring a vasopressor (with or without vasopressin) and/or Hypoxia requiring high-flow oxygen by nasal cannula, face mask, non-rebreather mask, or Venturi mask.	Withhold EPKINLY and manage per current practice guidelines, which may include intensive care. Ensure CRS symptoms are resolved prior to the next dose of EPKINLY. Administer premedication prior to next dose of EPKINLY. Hospitalize for the next dose of EPKINLY.
Grade 3		Recurrent Grade 3 CRS Permanently discontinue EPKINLY. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care.
Grade 4	Temperature ≥ 100.4°F (38°C) with: Hypotension requiring multiple vasopressors (excluding vasopressin) and/or Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation).	Permanently discontinue EPKINLY. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care.

Immune Effector Cell-Associated Neurological Toxicity Syndrome (ICANS)

Monitor patients for signs and symptoms of ICANS

[see Warnings and Precautions (5.2)]

. At the first sign of ICANS, withhold EPKINLY and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for ICANS

[see Warnings and Precautions (5.2)].

Manage ICANS according to the recommendations in Table 8 and consider further management per current practice guidelines.

Table 8: Recommendations for Management of Immune Effector Cell-Associated Neurotoxicity Syndrome
GradeBased on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS.	Presenting SymptomsManagement is determined by the most severe event, not attributable to any other cause.	Actions
Grade 1	ICE score 7-9If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (names 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., "show me 2 fingers" or "close your eyes and stick out your tongue" = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points., Or depressed level of consciousnessNot attributable to any other cause.: awakens spontaneously.	Withhold EPKINLY until ICANS resolves.See Table 4or Table 5for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)]. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis.
Grade 2	ICE score 3-6 , Or depressed level of consciousness : awakens to voice.	Withhold EPKINLY until ICANS resolves. Administer dexamethasoneAll references to dexamethasone administration are dexamethasone or equivalent.10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis.
Grade 3	ICE score 0-2 , Or depressed level of consciousness : awakens only to tactile stimulus, Or seizures, either: Any clinical seizure, focal or generalized, that resolves rapidly, or Non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, Or raised intracranial pressure: focal/local edema on neuroimaging.	First Occurrence of Grade 3 ICANS Withhold EPKINLY until ICANS resolves. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care.
Grade 3		Recurrent Grade 3 ICANS Permanently discontinue EPKINLY Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care.
Grade 4	ICE score 0 , Or depressed level of consciousness : either: Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or Stupor or coma Or seizures, either: Life-threatening prolonged seizure (> 5 minutes), or Repetitive clinical or electrical seizures without return to baseline in between, Or motor findings : Deep focal motor weakness, such as hemiparesis or paraparesis, or raised intracranial pressure/cerebral edema, with signs/symptoms such as: Diffuse cerebral edema on neuroimaging, or Decerebrate or decorticate posturing, or Cranial nerve VI palsy, or Papilledema, or Cushing's triad.	Permanently discontinue EPKINLY. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Alternatively, consider administration of methylprednisolone 1,000 mg per day intravenously and continue methylprednisolone 1,000 mg per day intravenously for 2 or more days. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care.

Table 9: Recommended Dosage Modifications for Other Adverse Reactions when EPKINLY is Given as Monotherapy
Adverse ReactionBased on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.	Severity	Action
Infections [see Warnings and Precautions (5.3)]	Grades 1-4	Withhold EPKINLY in patients with active infection, until the infection resolves.See Table 4or Table 5for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)]. For Grade 4, consider permanent discontinuation of EPKINLY.
Neutropenia [see Warnings and Precautions (5.4)]	Absolute neutrophil count less than 0.5 × 10⁹/L	Withhold EPKINLY until absolute neutrophil count is 0.5 × 10⁹/L or higher.
Thrombocytopenia [see Warnings and Precautions (5.4)]	Platelet count less than 50 × 10⁹/L	Withhold EPKINLY until platelet count is 50 × 10⁹/L or higher.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3 or higher	Withhold EPKINLY until the toxicity resolves to Grade 1 or baseline.

Table 10: Recommended Dosage Modifications for Other Adverse Reactions when EPKINLY is Given in Combination with Lenalidomide and Rituximab
Adverse Reaction	SeverityBased on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.	ActionRefer to lenalidomide prescribing information for additional toxicity guidelines.
Neutropenia [see Warnings and Precautions (5.4)]	Absolute neutrophil count less than 0.5 × 10⁹/L	Consider G-CSF. Withhold EPKINLY until absolute neutrophil count is 1 × 10⁹/L or higher.See Table 4or 5for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3)]. Withhold lenalidomide for remainder of cycle. On Day 1 of next cycle, the dose of lenalidomide may be maintained if neutropenia was the only toxicity limiting lenalidomide dosing.
Febrile Neutropenia [see Warnings and Precautions (5.4)]	Grade 3 or higher	Consider G-CSF. Withhold EPKINLY until fever resolves and absolute neutrophil count is 1 × 10⁹/L or higher. Withhold lenalidomide for remainder of cycle. On Day 1 of next cycle, dose of lenalidomide may be maintained if febrile neutropenia was the only toxicity limiting lenalidomide dosing.
Thrombocytopenia [see Warnings and Precautions (5.4)]	Platelet count less than 50 × 10⁹/L	Withhold EPKINLY until platelet count is 50 × 10⁹/L or higher. Withhold lenalidomide for remainder of cycle. Decrease lenalidomide dose for next cycle.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3	For first episode, withhold EPKINLY until improvement to Grade 2 or less or resolution to baseline. For second episode, permanently discontinue EPKINLY if clinically indicated.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 4	Permanently discontinue EPKINLY at discretion of healthcare provider.

)

11/2025

Warnings and Precautions (

5.1 Cytokine Release Syndrome

EPKINLY can cause CRS, including serious or fatal reactions

[see Adverse Reactions (6.1)]

Relapsed or Refractory Large B-cell Lymphoma

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

[see Dosage and Administration (2.1, 2.2)].

Relapsed or Refractory Follicular Lymphoma

For patients with FL, assess whether hospitalization or outpatient monitoring for the first 48 mg dose is appropriate based on comorbidities or other situational factors

[see Dosage and Administration (2.1)]

. During outpatient monitoring after the first 48 mg dose, patients should remain in proximity to a healthcare facility that can assess and manage CRS.

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

[see Dosage and Administration (2.2, 2.3, 2.4)]

[see Dosage and Administration (2.6)]

5.2 Immune Effector Cell-Associated Neurotoxicity Syndrome

EPKINLY can cause life-threatening and fatal immune effector cell-associated neurotoxicity syndrome (ICANS)

[see Adverse Reactions (6.1)]

Relapsed or Refractory Large B-cell Lymphoma

Relapsed or Refractory Follicular Lymphoma

Among patients with FL who received EPINKLY at the recommended dosage schedule in combination with lenalidomide and rituximab in EPCORE FL-1, ICANS occurred in 0.8% (1/131, Grade 1).

[see Dosage and Administration (2.6)]

5.3 Infections

EPKINLY can cause fatal and serious infections

[see Adverse Reactions (6.1)]

Serious infections, including opportunistic infections, were reported in 15% of patients with LBCL receiving EPKINLY at the recommended dosage schedule in EPCORE NHL-1 and were most commonly due to sepsis (4.5%) and pneumonia (3.2%). Fatal infections occurred in 1.3% of patients and were due to COVID-19.

Serious infections, including opportunistic infections, were reported in 40% of patients with FL receiving EPKINLY monotherapy following the 2-step up dosage schedule in EPCORE NHL-1 and were most commonly due to COVID-19 (20%), pneumonia (13%), and urinary tract infections (3%). Fatal infections occurred in 6% of patients and included COVID-19 (5%), pneumonia (0.8%), and sepsis (0.8%).

Among 243 patients with FL who received EPKINLY in combination with lenalidomide and rituximab in EPCORE FL-1, serious infections occurred in 28% of patients. The most common serious infections were pneumonia (15%), COVID-19 (7%), opportunistic infections (5%) and upper respiratory infections (3.3%). The most common opportunistic infections of any grade were CMV infection (7%) and herpesvirus infection (7%).

Progressive multifocal leukoencephalopathy (PML), including fatal cases, has occurred in patients treated with EPKINLY. Across a broader clinical trial population, PML was reported in 0.4% (11/3072) of patients, including in the first-line treatment setting. Of the 11 cases of PML, six resulted in fatal outcomes and one was unresolved at the time of death.

Monitor patients for signs and symptoms of infection and treat appropriately. Avoid administration of EPKINLY in patients with active infections. Provide PJP prophylaxis during treatment with EPKINLY, and consider initiating prophylaxis against herpesvirus

[see Dosage and Administration (2.5)].

Withhold or consider permanent discontinuation of EPKINLY based on severity

[see Dosage and Administration (2.6)]

5.4 Cytopenias

EPKINLY can cause serious or severe cytopenias, including neutropenia, lymphopenia, anemia, and thrombocytopenia

[see Adverse Reactions (6.1)]

In patients with LBCL who received EPKINLY at the recommended dosage schedule, Grade 3 or 4 decreased neutrophils occurred in 32% (Grade 4, 14%), decreased hemoglobin in 12% (Grade 4, 0%), and decreased platelets in 12% (Grade 4, 7%) of patients. Febrile neutropenia occurred in 2.5% (Grade 4, 0.6%).

In patients with FL who received EPKINLY monotherapy following the 2-step up dosage schedule, Grade 3 or 4 decreased neutrophils occurred in 30% (Grade 4, 17%), decreased hemoglobin in 10% (Grade 4, 0%), and decreased platelets in 8% of patients (Grade 4, 4%). Febrile neutropenia occurred in 3.1% (Grade 4, 0%).

In patients with FL who received EPKINLY in combination with lenalidomide and rituximab, Grade 3 or 4 decreased neutrophils occurred in 67% (Grade 4, 41%), decreased lymphocytes in 62% (Grade 4, 13%), decreased hemoglobin in 7%, and decreased platelets in 10% (Grade 4, 4.1%) of patients. Febrile neutropenia occurred in 6% (Grade 4, 2.1%).

Monitor complete blood counts throughout treatment. Based on the severity of cytopenias, temporarily withhold or permanently discontinue EPKINLY

[see Dosage and Administration (2.6)].

Consider prophylactic granulocyte colony-stimulating factor administration as applicable.

)

11/2025

Warnings and Precautions, Infections (

5.3 Infections

EPKINLY can cause fatal and serious infections

[see Adverse Reactions (6.1)]

[see Dosage and Administration (2.5)].

Withhold or consider permanent discontinuation of EPKINLY based on severity

[see Dosage and Administration (2.6)]

)

9/2025

EPKINLY is a bispecific CD20-directed CD3 T-cell engager indicated:

For the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy. (
1.1 DLBCL and High-grade B-cell Lymphoma
EPKINLY is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy.
This indication is approved under accelerated approval based on response rate and durability of response
[see Clinical Studies (14.1)].
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
)

This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
In combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL). (
1.2 Follicular Lymphoma
EPKINLY is indicated in combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL).
EPKINLY is indicated as monotherapy for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.
)
As monotherapy for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy. (
1.2 Follicular Lymphoma
EPKINLY is indicated in combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL).
EPKINLY is indicated as monotherapy for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.
)

For subcutaneous injection only. (

2.2 Recommended Dosage

EPKINLY is for subcutaneous injection only.

The recommended DLBCL dosage for Cycle 1 consists of 2 step-up doses, and the recommended FL dosage (monotherapy or in combination with lenalidomide and rituximab) consists of 3 step-up doses.

EPKINLY as Monotherapy:

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

Table 1: EPKINLY Dosage Schedule for Patients with DLBCL or High-grade B-cell Lymphoma
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
DLBCL or High-grade B-cell Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	First full dose	48 mg
		22	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

Table 2: EPKINLY Dosage Schedule for Patients with FL when Given as Monotherapy
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

EPKINLY in Combination with Lenalidomide and Rituximab:

Administer EPKINLY in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurs first.

Table 3: EPKINLY Dosage Schedule in Combination with Lenalidomide and Rituximab for Patients with FL
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15, and 22	48 mg
	Cycles 4 to 12	1	48 mg

Administer EPKINLY in combination with lenalidomide 20 mg (Days 1 to 21 in Cycles 1 to 12) and rituximab 375 mg/m²(Cycles 1 to 5)

[see Clinical Studies (14.2)].

)

Recommended Dosage: (

2.2 Recommended Dosage

EPKINLY is for subcutaneous injection only.

The recommended DLBCL dosage for Cycle 1 consists of 2 step-up doses, and the recommended FL dosage (monotherapy or in combination with lenalidomide and rituximab) consists of 3 step-up doses.

EPKINLY as Monotherapy:

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

Table 1: EPKINLY Dosage Schedule for Patients with DLBCL or High-grade B-cell Lymphoma
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
DLBCL or High-grade B-cell Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	First full dose	48 mg
		22	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

Table 2: EPKINLY Dosage Schedule for Patients with FL when Given as Monotherapy
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15 and 22	48 mg
	Cycles 4 to 9	1 and 15	48 mg
	Cycle 10 and beyond	1	48 mg

EPKINLY in Combination with Lenalidomide and Rituximab:

Administer EPKINLY in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurs first.

Table 3: EPKINLY Dosage Schedule in Combination with Lenalidomide and Rituximab for Patients with FL
Indication	CycleCycle = 28 days.	Day	Dose of EPKINLY
Follicular Lymphoma	Cycle 1	1	Step-up dose 1	0.16 mg
		8	Step-up dose 2	0.8 mg
		15	Step-up dose 3	3 mg
		22	First full dose	48 mg
	Cycles 2 and 3	1, 8, 15, and 22	48 mg
	Cycles 4 to 12	1	48 mg

Administer EPKINLY in combination with lenalidomide 20 mg (Days 1 to 21 in Cycles 1 to 12) and rituximab 375 mg/m²(Cycles 1 to 5)

[see Clinical Studies (14.2)].

)

DLBCL and High-grade B-cell Lymphoma

Cycle Cycle = 28 days	Day	Dose of EPKINLY
Cycle 1	1	Step-up dose 1	0.16 mg
	8	Step-up dose 2	0.8 mg
	15	First full dose	48 mg
	22	48 mg
Cycles 2 and 3	1, 8, 15 and 22	48 mg
Cycles 4 to 9	1 and 15	48 mg
Cycle 10 and beyond	1	48 mg

EPKINLY as Monotherapy for FL

CycleCycle = 28 days	Day	Dose of EPKINLY
Cycle 1	1	Step-up dose 1	0.16 mg
	8	Step-up dose 2	0.8 mg
	15	Step-up dose 3	3 mg
	22	First full dose	48 mg
Cycles 2 and 3	1, 8, 15 and 22	48 mg
Cycles 4 to 9	1 and 15	48 mg
Cycle 10 and beyond	1	48 mg

EPKINLY in Combination with Lenalidomide and Rituximab for FL

CycleCycle = 28 days	Day	Dose of EPKINLY
Cycle 1	1	Step-up dose 1	0.16 mg
	8	Step-up dose 2	0.8 mg
	15	Step-up dose 3	3 mg
	22	First full dose	48 mg
Cycles 2 and 3	1, 8, 15, and 22	48 mg
Cycles 4 to 12	1	48 mg

Monitor all patients for signs and symptoms of CRS and ICANS. (
2.1 Important Dosing Information
- Certain doses of EPKINLY require
  dilution
  prior to administration. There are 2 available methods to prepare
  diluted
  EPKINLY:
  Empty sterile vial method as described in subsection 2.7
  [see Dosage and Administration (2.7)]
  , or
  Sterile syringe method as described in subsection 2.8
  [see Dosage and Administration (2.8)]
  .
- Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution.
  [see Dosage and Administration (2.9)]
  .
- EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS
  [see Warnings and Precautions (5.1, 5.2)]
  .
- Administer EPKINLY to well-hydrated patients.
- Premedicate before each dose in Cycle 1
  [see Dosage and Administration (2.4)]
  .
- Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS
  [see Dosage and Administration (2.2)]
  .
- Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms
  [see Dosage and Administration (2.6)]
  .
  For patients with DLBCL or high-grade B-cell lymphoma:
  
  Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg
  [see Dosage and Administration (2.2)].
  For patients with FL:
  
  Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the Cycle 1 Day 22 dosage of 48 mg
  [see Dosage and Administration (2.2)
  ].
)
Patients with DLBCL or high-grade B-cell lymphoma should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg. (
2.1 Important Dosing Information
- Certain doses of EPKINLY require
  dilution
  prior to administration. There are 2 available methods to prepare
  diluted
  EPKINLY:
  Empty sterile vial method as described in subsection 2.7
  [see Dosage and Administration (2.7)]
  , or
  Sterile syringe method as described in subsection 2.8
  [see Dosage and Administration (2.8)]
  .
- Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution.
  [see Dosage and Administration (2.9)]
  .
- EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS
  [see Warnings and Precautions (5.1, 5.2)]
  .
- Administer EPKINLY to well-hydrated patients.
- Premedicate before each dose in Cycle 1
  [see Dosage and Administration (2.4)]
  .
- Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS
  [see Dosage and Administration (2.2)]
  .
- Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms
  [see Dosage and Administration (2.6)]
  .
  For patients with DLBCL or high-grade B-cell lymphoma:
  
  Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg
  [see Dosage and Administration (2.2)].
  For patients with FL:
  
  Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the Cycle 1 Day 22 dosage of 48 mg
  [see Dosage and Administration (2.2)
  ].
)For patients with FL, assess whether hospitalization or outpatient monitoring is appropriate after administration of the Cycle 1 Day 22 dosage of 48 mg. (
2.1 Important Dosing Information
- Certain doses of EPKINLY require
  dilution
  prior to administration. There are 2 available methods to prepare
  diluted
  EPKINLY:
  Empty sterile vial method as described in subsection 2.7
  [see Dosage and Administration (2.7)]
  , or
  Sterile syringe method as described in subsection 2.8
  [see Dosage and Administration (2.8)]
  .
- Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution.
  [see Dosage and Administration (2.9)]
  .
- EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS
  [see Warnings and Precautions (5.1, 5.2)]
  .
- Administer EPKINLY to well-hydrated patients.
- Premedicate before each dose in Cycle 1
  [see Dosage and Administration (2.4)]
  .
- Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS
  [see Dosage and Administration (2.2)]
  .
- Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms
  [see Dosage and Administration (2.6)]
  .
  For patients with DLBCL or high-grade B-cell lymphoma:
  
  Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg
  [see Dosage and Administration (2.2)].
  For patients with FL:
  
  Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the Cycle 1 Day 22 dosage of 48 mg
  [see Dosage and Administration (2.2)
  ].
)

Administer premedications, post-medications, and prophylaxis as recommended. (

2.4 Recommended Pre- and Post-Administration Medications

Administer pre- and post-administration medications as outlined in Table 6 to reduce the risk of CRS

[see Warnings and Precautions (5.1)]

Table 6: EPKINLY Pre- and Post-Administration Medications
Cycle	Patients requiring medication	Medication	Administration
Cycle 1	All patients	DexamethasoneDexamethasone is the preferred corticosteroid when available.(15 mg oral or intravenous) or Prednisolone (100 mg oral or intravenous) or equivalent	30-120 minutes prior to each weekly administration of EPKINLY And for three consecutive days following each weekly administration of EPKINLY in Cycle 1
Cycle 1	All patients	Diphenhydramine (50 mg oral or intravenous) or equivalent Acetaminophen (650 mg to 1,000 mg oral)	30-120 minutes prior to each weekly administration of EPKINLY
Cycle 2+	Patients who experienced Grade 2 or 3Patients will be permanently discontinued from EPKINLY after Grade 4 CRS.CRS with previous dose	Dexamethasone (15 mg oral or intravenous) or Prednisolone (100 mg oral or intravenous) or equivalent	30-120 minutes prior to next administration of EPKINLY after a Grade 2 or 3 CRS event And for three consecutive days following the next administration of EPKINLY until EPKINLY is given without subsequent CRS of Grade 2 or higher

2.5 Recommended Prophylaxis

Pneumocystis jirovecii pneumonia (PJP)

Provide PJP prophylaxis during treatment with EPKINLY.

Herpesvirus

Consider providing prophylaxis against herpesvirus during treatment with EPKINLY to prevent herpes simplex and herpes zoster.

Thromboprophylaxis

Refer to the lenalidomide prescribing information for recommendations on prophylaxis for venous and arterial thrombotic events.

)

Dosages of EPKINLY 0.16 mg and 0.8 mg require dilution prior to administration. (
2.7 Preparation of Diluted EPKINLY using the Vial Method
Read this entire section carefully before preparation of EPKINLY. Certain doses of EPKINLY require
dilution
prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to improper dose. This section describes preparation of diluted EPKINLY using empty sterile vial method. For preparation using sterile syringe method, see subsection 2.8
[see Dosage and Administration (2.8)]
.
EPKINLY is prepared and administered by a healthcare provider as a subcutaneous injection. The administration of EPKINLY takes place over the course of 28-day cycles, following the step-up dosage schedule in Section 2.2.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Use aseptic technique to prepare EPKINLY. Filtration of the diluted solution is not required.
0.16 mg Dose Preparation Instructions (
2 dilutions required
) – Empty Sterile Vial Method
Use an appropriately sized syringe, vial, and needle for each transfer step.
Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.
Allow the vial to come to room temperature for no more than 1 hour.
Gently swirl the EPKINLY vial.
DO NOT
invert, vortex, or vigorously shake the vial.Label an appropriately sized empty vial as
"Dilution A."
Transfer
0.8 mL of EPKINLY
into the
Dilution A
vial.
Transfer
4.2 mL of 0.9% Sodium Chloride Injection
into the
Dilution A
vial.

The initially diluted solution contains 0.8 mg/mL of EPKINLY.
Gently swirl the
Dilution A
vial for 30 to 45 seconds.Label an appropriately sized empty vial as
"Dilution B."
Transfer
2 mL of solution
from the
Dilution A
vial into the
Dilution B
vial. The
Dilution A
vial is no longer needed.
Transfer
8 mL of 0.9% Sodium Chloride Injection
into the
Dilution B
vial to make a final concentration of 0.16 mg/mL.
Gently swirl the
Dilution B
vial for 30 to 45 seconds.Withdraw
1 mL of the diluted EPKINLY
from the
Dilution B
vial into a syringe.Label the syringe with the dose strength (0.16 mg) and the time of day.
1. Prepare EPKINLY vial
a.b.c.
2. Perform first dilution
a.b.c.d.
3. Perform second dilution
a.b.c.d.
4. Withdraw dose
a.
5. Label syringe
a.
Discard the vial containing unused EPKINLY.
0.8 mg Dose Preparation Instructions (
1 dilution required
) – Empty Sterile Vial Method
Use an appropriately sized syringe, vial, and needle for each transfer step.
Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.
Allow the vial to come to room temperature for no more than 1 hour.
Gently swirl the EPKINLY vial.
DO NOT
invert, vortex, or vigorously shake the vial.Label an appropriately sized empty vial as "
Dilution A
".
Transfer
0.8 mL of EPKINLY
into the
Dilution A
vial.
Transfer
4.2 mL of 0.9% Sodium Chloride Injection
into the
Dilution A
vial to make a final concentration of 0.8 mg/mL.
Gently swirl the
Dilution A
vial for 30 to 45 seconds.Withdraw
1 mL of the diluted EPKINLY
from the
Dilution A
vial into a syringe.Label the syringe with the dose strength (0.8 mg) and the time of day.
1. Prepare EPKINLY vial
a.b.c.
2. Perform dilution
a.b.c.d.
3. Withdraw dose
a.
4. Label syringe
a.
Discard the vial containing unused EPKINLY.
,
2.8 Preparation of Diluted EPKINLY using the Syringe Method
Read this entire section carefully before preparation of EPKINLY. Certain doses of EPKINLY require
dilution
prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to improper dose.
EPKINLY is prepared and administered by a healthcare provider as a subcutaneous injection. The administration of EPKINLY takes place over the course of 28-day cycles, following the step-up dosage schedule in Section 2.2.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Use aseptic technique to prepare EPKINLY. Filtration of the diluted solution is not required.
0.16 mg Dose Preparation Instructions (
2 dilutions required
) – Sterile Syringe Method
Use an appropriately sized syringe and needle for each transfer step.
Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.
Allow the vial to come to room temperature for no more than 1 hour.
Gently swirl the EPKINLY vial.
DO NOT
invert, vortex, or vigorously shake the vial.Label an appropriately sized syringe as
"Dilution A."
Withdraw
4.2 mL of 0.9% Sodium Chloride Injection
into the
Dilution A
syringe. Include approximately 0.2 mL air in the syringe.
In a new syringe labeled as
"Syringe 1"
, withdraw
0.8 mL of EPKINLY
.
Connect the two syringes and push the
0.8 mL of EPKINLY
into the
Dilution A
syringe. The initially diluted solution contains 0.8 mg/mL of EPKINLY
Gently mix by inverting the connected syringes 180 degrees 5 times.
Disconnect the syringes and discard
Syringe 1
.Label an appropriately sized syringe as
"Dilution B."
Withdraw
8 mL of 0.9% Sodium Chloride Injection
into the
Dilution B
syringe. Include approximately 0.2 mL air in the syringe.
Label another appropriately sized syringe as
"Syringe 2."
Connect
Syringe 2
to the
Dilution A
syringe and transfer
2 mL of solution
into
Syringe 2
. The
Dilution A
syringe is no longer needed.
Connect
Syringe 2
to the
Dilution B
syringe and push the
2 mL of solution
into the
Dilution B
syringe to make a final concentration of 0.16 mg/mL.
Gently mix by inverting the connected syringes 180 degrees 5 times.
Disconnect the syringes and discard
Syringe 2
.Connect and transfer
1 mL of the diluted EPKINLY
from the
Dilution B
syringe into a new syringe. The
Dilution B
syringe is no longer neededLabel the syringe with the dose strength (0.16 mg) and the time of day.
1. Prepare EPKINLY vial
a.b.c.
2. Perform first dilution
a.b.c.d.e.f.
3. Perform second dilution
a.b.c.d.e.f.g.
4. Withdraw dose
a.
5. Label syringe
a.
Discard the vial containing unused EPKINLY.
0.8 mg Dose Preparation Instructions (
1 dilution required
) – Sterile Syringe Method
Use an appropriately sized syringe and needle for each transfer step.
Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.
Allow the vial to come to room temperature for no more than 1 hour.
Gently swirl the EPKINLY vial.
DO NOT
invert, vortex, or vigorously shake the vial.Label an appropriately sized syringe as
"Dilution A."
Withdraw
4.2 mL of 0.9% Sodium Chloride Injection
into the
Dilution A
syringe. Include approximately 0.2 mL air in the syringe.
In a new syringe labeled as "
Syringe 1
", withdraw
0.8 mL of EPKINLY
.
Connect the two syringes and push the
0.8 mL of EPKINLY
into the
Dilution A
syringe to make a final concentration of 0.8 mg/mL.
Gently mix by inverting the connected syringes 180 degrees 5 times.
Disconnect the syringes and discard
Syringe 1
.Connect a new syringe to the
Dilution A
syringe and transfer
1 mL of the diluted EPKINLY
into the new syringe. The
Dilution A
syringe is no longer needed.Label the syringe with the dose strength (0.8 mg) and the time of day.
1. Prepare EPKINLY vial
a.b.c.
2. Perform dilution
a.b.c.d.e.f.
3. Withdraw dose
a.
4. Label syringe
a.
Discard the vial containing unused EPKINLY.
)
See Full Prescribing Information for instructions on preparation and administration. (
2.7 Preparation of Diluted EPKINLY using the Vial Method
Read this entire section carefully before preparation of EPKINLY. Certain doses of EPKINLY require
dilution
prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to improper dose. This section describes preparation of diluted EPKINLY using empty sterile vial method. For preparation using sterile syringe method, see subsection 2.8
[see Dosage and Administration (2.8)]
.
EPKINLY is prepared and administered by a healthcare provider as a subcutaneous injection. The administration of EPKINLY takes place over the course of 28-day cycles, following the step-up dosage schedule in Section 2.2.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Use aseptic technique to prepare EPKINLY. Filtration of the diluted solution is not required.
0.16 mg Dose Preparation Instructions (
2 dilutions required
) – Empty Sterile Vial Method
Use an appropriately sized syringe, vial, and needle for each transfer step.
Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.
Allow the vial to come to room temperature for no more than 1 hour.
Gently swirl the EPKINLY vial.
DO NOT
invert, vortex, or vigorously shake the vial.Label an appropriately sized empty vial as
"Dilution A."
Transfer
0.8 mL of EPKINLY
into the
Dilution A
vial.
Transfer
4.2 mL of 0.9% Sodium Chloride Injection
into the
Dilution A
vial.

The initially diluted solution contains 0.8 mg/mL of EPKINLY.
Gently swirl the
Dilution A
vial for 30 to 45 seconds.Label an appropriately sized empty vial as
"Dilution B."
Transfer
2 mL of solution
from the
Dilution A
vial into the
Dilution B
vial. The
Dilution A
vial is no longer needed.
Transfer
8 mL of 0.9% Sodium Chloride Injection
into the
Dilution B
vial to make a final concentration of 0.16 mg/mL.
Gently swirl the
Dilution B
vial for 30 to 45 seconds.Withdraw
1 mL of the diluted EPKINLY
from the
Dilution B
vial into a syringe.Label the syringe with the dose strength (0.16 mg) and the time of day.
1. Prepare EPKINLY vial
a.b.c.
2. Perform first dilution
a.b.c.d.
3. Perform second dilution
a.b.c.d.
4. Withdraw dose
a.
5. Label syringe
a.
Discard the vial containing unused EPKINLY.
0.8 mg Dose Preparation Instructions (
1 dilution required
) – Empty Sterile Vial Method
Use an appropriately sized syringe, vial, and needle for each transfer step.
Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.
Allow the vial to come to room temperature for no more than 1 hour.
Gently swirl the EPKINLY vial.
DO NOT
invert, vortex, or vigorously shake the vial.Label an appropriately sized empty vial as "
Dilution A
".
Transfer
0.8 mL of EPKINLY
into the
Dilution A
vial.
Transfer
4.2 mL of 0.9% Sodium Chloride Injection
into the
Dilution A
vial to make a final concentration of 0.8 mg/mL.
Gently swirl the
Dilution A
vial for 30 to 45 seconds.Withdraw
1 mL of the diluted EPKINLY
from the
Dilution A
vial into a syringe.Label the syringe with the dose strength (0.8 mg) and the time of day.
1. Prepare EPKINLY vial
a.b.c.
2. Perform dilution
a.b.c.d.
3. Withdraw dose
a.
4. Label syringe
a.
Discard the vial containing unused EPKINLY.
,
2.8 Preparation of Diluted EPKINLY using the Syringe Method
Read this entire section carefully before preparation of EPKINLY. Certain doses of EPKINLY require
dilution
prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to improper dose.
EPKINLY is prepared and administered by a healthcare provider as a subcutaneous injection. The administration of EPKINLY takes place over the course of 28-day cycles, following the step-up dosage schedule in Section 2.2.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Use aseptic technique to prepare EPKINLY. Filtration of the diluted solution is not required.
0.16 mg Dose Preparation Instructions (
2 dilutions required
) – Sterile Syringe Method
Use an appropriately sized syringe and needle for each transfer step.
Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.
Allow the vial to come to room temperature for no more than 1 hour.
Gently swirl the EPKINLY vial.
DO NOT
invert, vortex, or vigorously shake the vial.Label an appropriately sized syringe as
"Dilution A."
Withdraw
4.2 mL of 0.9% Sodium Chloride Injection
into the
Dilution A
syringe. Include approximately 0.2 mL air in the syringe.
In a new syringe labeled as
"Syringe 1"
, withdraw
0.8 mL of EPKINLY
.
Connect the two syringes and push the
0.8 mL of EPKINLY
into the
Dilution A
syringe. The initially diluted solution contains 0.8 mg/mL of EPKINLY
Gently mix by inverting the connected syringes 180 degrees 5 times.
Disconnect the syringes and discard
Syringe 1
.Label an appropriately sized syringe as
"Dilution B."
Withdraw
8 mL of 0.9% Sodium Chloride Injection
into the
Dilution B
syringe. Include approximately 0.2 mL air in the syringe.
Label another appropriately sized syringe as
"Syringe 2."
Connect
Syringe 2
to the
Dilution A
syringe and transfer
2 mL of solution
into
Syringe 2
. The
Dilution A
syringe is no longer needed.
Connect
Syringe 2
to the
Dilution B
syringe and push the
2 mL of solution
into the
Dilution B
syringe to make a final concentration of 0.16 mg/mL.
Gently mix by inverting the connected syringes 180 degrees 5 times.
Disconnect the syringes and discard
Syringe 2
.Connect and transfer
1 mL of the diluted EPKINLY
from the
Dilution B
syringe into a new syringe. The
Dilution B
syringe is no longer neededLabel the syringe with the dose strength (0.16 mg) and the time of day.
1. Prepare EPKINLY vial
a.b.c.
2. Perform first dilution
a.b.c.d.e.f.
3. Perform second dilution
a.b.c.d.e.f.g.
4. Withdraw dose
a.
5. Label syringe
a.
Discard the vial containing unused EPKINLY.
0.8 mg Dose Preparation Instructions (
1 dilution required
) – Sterile Syringe Method
Use an appropriately sized syringe and needle for each transfer step.
Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.
Allow the vial to come to room temperature for no more than 1 hour.
Gently swirl the EPKINLY vial.
DO NOT
invert, vortex, or vigorously shake the vial.Label an appropriately sized syringe as
"Dilution A."
Withdraw
4.2 mL of 0.9% Sodium Chloride Injection
into the
Dilution A
syringe. Include approximately 0.2 mL air in the syringe.
In a new syringe labeled as "
Syringe 1
", withdraw
0.8 mL of EPKINLY
.
Connect the two syringes and push the
0.8 mL of EPKINLY
into the
Dilution A
syringe to make a final concentration of 0.8 mg/mL.
Gently mix by inverting the connected syringes 180 degrees 5 times.
Disconnect the syringes and discard
Syringe 1
.Connect a new syringe to the
Dilution A
syringe and transfer
1 mL of the diluted EPKINLY
into the new syringe. The
Dilution A
syringe is no longer needed.Label the syringe with the dose strength (0.8 mg) and the time of day.
1. Prepare EPKINLY vial
a.b.c.
2. Perform dilution
a.b.c.d.e.f.
3. Withdraw dose
a.
4. Label syringe
a.
Discard the vial containing unused EPKINLY.
,
2.9 Preparation of 3 mg and 48 mg EPKINLY Doses
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Use aseptic technique to prepare EPKINLY.
3 mg Dose Preparation Instructions
(No dilution required)
EPKINLY 3 mg dose is required for patients with FL only
[see Dosage and Administration (2.2)]
.
Retrieve one 4 mg/0.8 mL EPKINLY vial from the refrigerator.
Allow the vial to come to room temperature for no more than 1 hour.
Gently swirl the EPKINLY vial.Withdraw
0.6 mL of EPKINLY
into a syringe.Label the syringe with the dose strength (3 mg) and the time of day.
1. Prepare EPKINLY vial
a.b.c.
DO NOT
invert, vortex, or vigorously shake the vial.
2. Withdraw dose
a.
3. Label syringe
a.
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.
Retrieve one 48 mg/0.8 mL EPKINLY vial from the refrigerator.
Allow the vial to come to room temperature for no more than 1 hour.
Gently swirl the EPKINLY vial.Withdraw
0.8 mL of EPKINLY
into a syringe.Label the syringe with the dose strength (48 mg) and the time of day.
1. Prepare EPKINLY vial
a.b.c.
DO NOT
invert, vortex, or vigorously shake the vial.
2. Withdraw dose
a.
3. Label syringe
a.
Discard the vial containing unused EPKINLY.
,
2.10 Storage and Administration
Storage of EPKINLY Solution in the Syringe
Use EPKINLY solution in the syringe immediately. If not used immediately, store the solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at room temperature at 20°C to 25°C (68°F to 77°F) for up to 12 hours. The total storage time from the start of dose preparation to administration should not exceed 24 hours. Protect from direct sunlight. Discard unused EPKINLY solution beyond the allowable storage time.
Administration of EPKINLY
To minimize injection pain, allow EPKINLY solution to equilibrate to room temperature for no more than 1 hour before administration. Inject the required volume of EPKINLY into the subcutaneous tissue of the lower part of the abdomen (preferred injection site) or the thigh.
Change of injection site from the left or right side or vice versa is recommended, especially during the weekly administrations (Cycles 1 to 3). Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, or not intact.
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Lactation

: Advise not to breastfeed. (

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, and there is potential for epcoritamab-bysp absorption leading to serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with EPKINLY and for 4 months after the last dose.

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