Imdelltra

(Tarlatamab-Dlle)

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Dosage & Administration

Administer as an intravenous infusion over 1 hour. (

2.2 Recommended Dosage and Administration

* Administer IMDELLTRA as an intravenous infusion for one hour.
*

The recommended step-up dose and schedule for IMDELLTRA is provided in Table 1. Administer step-up dose and schedule on Cycle 1 Day 1 to reduce the incidence and severity of CRS.

After step-up dose and schedule on Cycle 1 Day 1, administer IMDELLTRA every 2 weeks until disease progression or unacceptable toxicity.

Table 1. Recommended Dose and Schedule of IMDELLTRA
Dosing Schedule	Day	Dose of IMDELLTRA	Administration Instructions	Recommended Monitoring
Note: See Table 4for recommendation on restarting IMDELLTRA after dose delays.
Step-up Dose and Schedule Cycle 1	Day 1Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3.	Step-up dose 1 mg	Administer IMDELLTRA as a 1-hour intravenous infusion in an appropriate healthcare setting.	Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the IMDELLTRA infusion accompanied by a caregiver.
	Day 8	10 mg
	Day 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusionExtended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥ 2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5and 6for monitoring recommendations.
Cycle 2	Day 1 and 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion .
Cycles 3 and 4	Day 1 and 15	10 mg		Observe patients for 3-4 hours post IMDELLTRA infusion .
Cycle 5 and subsequent infusions	Day 1 and 15	10 mg		Observe patients for 2 hours post IMDELLTRA infusion .

Administration

The intravenous (IV) catheter for concomitant medications administration can be used to administer the IMDELLTRA infusion.

To ensure patency, flush the IV catheter over 3 to 5 minutes using 0.9% Sodium Chloride for Injection.

* Administer the reconstituted and diluted IMDELLTRA as a 1-hour intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. Flush the IV-line upon completion of the IMDELLTRA infusion.

Table 2 provides the infusion duration and rate.

Table 2. IMDELLTRA Infusion Duration and Rate
Infusion Duration for 250 mL IV Preparation	Infusion Rate
1 hour	250 mL/hour

)

* Administer IMDELLTRA according to the step

up dosing schedule in Table 1 to reduce the risk of cytokine release syndrome. (

2.2 Recommended Dosage and Administration

* Administer IMDELLTRA as an intravenous infusion for one hour.
*

The recommended step-up dose and schedule for IMDELLTRA is provided in Table 1. Administer step-up dose and schedule on Cycle 1 Day 1 to reduce the incidence and severity of CRS.

After step-up dose and schedule on Cycle 1 Day 1, administer IMDELLTRA every 2 weeks until disease progression or unacceptable toxicity.

Table 1. Recommended Dose and Schedule of IMDELLTRA
Dosing Schedule	Day	Dose of IMDELLTRA	Administration Instructions	Recommended Monitoring
Note: See Table 4for recommendation on restarting IMDELLTRA after dose delays.
Step-up Dose and Schedule Cycle 1	Day 1Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3.	Step-up dose 1 mg	Administer IMDELLTRA as a 1-hour intravenous infusion in an appropriate healthcare setting.	Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the IMDELLTRA infusion accompanied by a caregiver.
	Day 8	10 mg
	Day 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusionExtended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥ 2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5and 6for monitoring recommendations.
Cycle 2	Day 1 and 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion .
Cycles 3 and 4	Day 1 and 15	10 mg		Observe patients for 3-4 hours post IMDELLTRA infusion .
Cycle 5 and subsequent infusions	Day 1 and 15	10 mg		Observe patients for 2 hours post IMDELLTRA infusion .

Administration

The intravenous (IV) catheter for concomitant medications administration can be used to administer the IMDELLTRA infusion.

To ensure patency, flush the IV catheter over 3 to 5 minutes using 0.9% Sodium Chloride for Injection.

Table 2 provides the infusion duration and rate.

Table 2. IMDELLTRA Infusion Duration and Rate
Infusion Duration for 250 mL IV Preparation	Infusion Rate
1 hour	250 mL/hour

)
* Administer concomitant medications as recommended. (

2.3 Recommended Concomitant Medications for IMDELLTRA Administration for Cycle 1 Day 1 and Cycle 1 Day 8

Administer recommended concomitant medications for IMDELLTRA during Cycle 1 Day 1 and Cycle 1 Day 8 as presented in Table 3 to reduce the risk of CRS

[see Warnings and Precautions (5.1)]

Table 3. Recommended Concomitant Medications for IMDELLTRA Administration for Cycle 1 Day 1 and Cycle 1 Day 8
Treatment Day	Medication	Administration
Cycle 1 Day 1 and Cycle 1 Day 8	Administer dexamethasone 8 mg intravenously (or equivalent)	Within 1 hour prior to IMDELLTRA administration
Cycle 1 Day 1 and Cycle 1 Day 8	Administer 1 liter of normal saline intravenously over 2 to 4 hours	Immediately after completion of IMDELLTRA infusion

)
* Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting.
* Recommend patients to remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from the start of the infusion with IMDELLTRA following Cycle 1 Day 1 and Cycle 1 Day 8 doses, accompanied by a caregiver. (

2.2 Recommended Dosage and Administration

* Administer IMDELLTRA as an intravenous infusion for one hour.
*

The recommended step-up dose and schedule for IMDELLTRA is provided in Table 1. Administer step-up dose and schedule on Cycle 1 Day 1 to reduce the incidence and severity of CRS.

After step-up dose and schedule on Cycle 1 Day 1, administer IMDELLTRA every 2 weeks until disease progression or unacceptable toxicity.

Table 1. Recommended Dose and Schedule of IMDELLTRA
Dosing Schedule	Day	Dose of IMDELLTRA	Administration Instructions	Recommended Monitoring
Note: See Table 4for recommendation on restarting IMDELLTRA after dose delays.
Step-up Dose and Schedule Cycle 1	Day 1Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3.	Step-up dose 1 mg	Administer IMDELLTRA as a 1-hour intravenous infusion in an appropriate healthcare setting.	Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the IMDELLTRA infusion accompanied by a caregiver.
	Day 8	10 mg
	Day 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusionExtended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥ 2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5and 6for monitoring recommendations.
Cycle 2	Day 1 and 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion .
Cycles 3 and 4	Day 1 and 15	10 mg		Observe patients for 3-4 hours post IMDELLTRA infusion .
Cycle 5 and subsequent infusions	Day 1 and 15	10 mg		Observe patients for 2 hours post IMDELLTRA infusion .

Administration

The intravenous (IV) catheter for concomitant medications administration can be used to administer the IMDELLTRA infusion.

To ensure patency, flush the IV catheter over 3 to 5 minutes using 0.9% Sodium Chloride for Injection.

Table 2 provides the infusion duration and rate.

Table 2. IMDELLTRA Infusion Duration and Rate
Infusion Duration for 250 mL IV Preparation	Infusion Rate
1 hour	250 mL/hour

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

2.2 Recommended Dosage and Administration

* Administer IMDELLTRA as an intravenous infusion for one hour.
*

The recommended step-up dose and schedule for IMDELLTRA is provided in Table 1. Administer step-up dose and schedule on Cycle 1 Day 1 to reduce the incidence and severity of CRS.

After step-up dose and schedule on Cycle 1 Day 1, administer IMDELLTRA every 2 weeks until disease progression or unacceptable toxicity.

Table 1. Recommended Dose and Schedule of IMDELLTRA
Dosing Schedule	Day	Dose of IMDELLTRA	Administration Instructions	Recommended Monitoring
Note: See Table 4for recommendation on restarting IMDELLTRA after dose delays.
Step-up Dose and Schedule Cycle 1	Day 1Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3.	Step-up dose 1 mg	Administer IMDELLTRA as a 1-hour intravenous infusion in an appropriate healthcare setting.	Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the IMDELLTRA infusion accompanied by a caregiver.
	Day 8	10 mg
	Day 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusionExtended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥ 2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5and 6for monitoring recommendations.
Cycle 2	Day 1 and 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion .
Cycles 3 and 4	Day 1 and 15	10 mg		Observe patients for 3-4 hours post IMDELLTRA infusion .
Cycle 5 and subsequent infusions	Day 1 and 15	10 mg		Observe patients for 2 hours post IMDELLTRA infusion .

Administration

The intravenous (IV) catheter for concomitant medications administration can be used to administer the IMDELLTRA infusion.

To ensure patency, flush the IV catheter over 3 to 5 minutes using 0.9% Sodium Chloride for Injection.

Table 2 provides the infusion duration and rate.

Table 2. IMDELLTRA Infusion Duration and Rate
Infusion Duration for 250 mL IV Preparation	Infusion Rate
1 hour	250 mL/hour

2.6 Preparation

Material Compatibility Information

* IV bags composed of ethyl vinyl acetate (EVA), polyolefin, and polyvinyl chloride (PVC) have been shown to be compatible with IMDELLTRA at the specified administration conditions.
* IV line and catheter materials composed of polyolefin, PVC, and polyurethane have been shown to be compatible with IMDELLTRA at the specified administration conditions.
* The use of Closed System Transfer Device (CSTD) is not recommended due to potential wrong dose medication error risk. Amgen has not performed compatibility testing of vial adaptor CSTDs with IMDELLTRA.

Step 1: Reconstitute IMDELLTRA with Sterile Water for Injection

* Table 8 provides the required amount of sterile water for injection required to reconstitute IMDELLTRA 1 mg and 10 mg vials.

Do not

use IV Solution Stabilizer (IVSS) to reconstitute IMDELLTRA

The IV Solution Stabilizer (IVSS) is used to coat the intravenous bag prior to addition of reconstituted IMDELLTRA to prevent adsorption of IMDELLTRA to IV bags and IV tubing.

Table 8. Required Amount of Sterile Water for Injection to Reconstitute IMDELLTRAEach vial contains overfill to allow for withdrawal of 1.1 mL (1 mg vial) or 4.2 mL (10 mg vial) after reconstitution to ensure delivery at the stated concentration of labeled vial strength.
IMDELLTRA Vial Strength	Amount of Sterile Water for Injection Needed to Reconstitute IMDELLTRA	Resulting Concentration
1 mg	1.3 mL	0.9 mg/mL
10 mg	4.4 mL	2.4 mg/mL

* Using a needle and syringe filled with the required amount of sterile water, inject the sterile water against the glass vial. Avoid injecting the water directly onto the powder to prevent foaming.
* Gently swirl the contents to mix. Do not shake.
* Inspect parenteral drug products for particulate matter and discoloration prior to administration. Inspect that the solution is clear to opalescent, colorless to slightly yellow. Do not use if the solution is cloudy or has particulates.
* Further dilute reconstituted IMDELLTRA.
* The reconstituted IMDELLTRA must be further diluted within 4 hours of reconstitution or discarded.

Prepare the infusion bag: Steps 2 to 5

Step 2 : Withdraw 0.9% Sodium Chloride for Injection

* Using a 250 mL prefilled bag of 0.9% Sodium Chloride for Injection, withdraw the amount of sodium chloride specified in Table 9 and discard.

Table 9. Required Amount of 0.9% Sodium Chloride to Withdraw from 250 mL IV Bag
IMDELLTRA Vial Strength	IMDELLTRA Dose	Volume of 0.9% Sodium Chloride to Withdraw From 250 mL IV Bag
1 mg	1 mg	14 mL
10 mg	10 mg	17 mL

Step 3: Add IV Solution Stabilizer to the infusion bag

* Inject 13 mL of IV Solution Stabilizer (IVSS) into the 250 mL 0.9% Sodium Chloride infusion bag

see Table 10

* Gently mix the contents of the infusion bag to avoid foaming. Do not shake.

Table 10. Required Amount of IV Solution Stabilizer (IVSS) to Add to IV Bag
IMDELLTRA Vial Strength	IMDELLTRA Dose	Volume of IV Solution Stabilizer (IVSS) to Add to IV Bag
1 mg	1 mg	13 mL
10 mg	10 mg	13 mL

Step 4: Dilute the reconstituted IMDELLTRA into the infusion bag

* Transfer the required volume of reconstituted IMDELLTRA listed in Table 11 to the infusion bag

(containing IV Solution Stabilizer)

NOTE: The final concentrations for the different strength vials are NOT the same following reconstitution and further dilution.

Table 11. Required Amount of Reconstituted IMDELLTRA to Add to 250 mL IV Bag
IMDELLTRA Vial Strength	IMDELLTRA Dose	Volume of Reconstituted IMDELLTRA to Add to 250 mL IV Bag
1 mg	1 mg	1.1 mL
10 mg	10 mg	4.2 mL

* Gently mix the contents of the bag. Do not shake.

Step 5: Remove air from IV bag

Remove air from the prepared IV bag using an empty syringe to avoid foaming.

Step 6: Prime IV tubing

* Prime intravenous tubing with either 0.9% Sodium Chloride for Injection or with the final prepared product.
* See Table 12for maximum storage time of prepared IMDELLTRA infusion.

Prepared IMDELLTRA Infusion Bag Storage Requirements

* Administer reconstituted and diluted IMDELLTRA immediately.
* Table 12 displays the maximum storage time for the prepared IMDELLTRA infusion bag.
* Maximum storage time includes total duration from the time of reconstitution of the vial of IMDELLTRA to the end of the infusion.

Table 12. Maximum Storage Time for Prepared IMDELLTRA Infusion Bag
	Room Temperature 20°C to 25°C (68°F to 77°F)	Refrigerated 2°C to 8°C (36°F to 46°F)
Prepared IMDELLTRA Infusion Bag	8 hours	7 days
* Discard the prepared IMDELLTRA infusion bag after maximum storage time (from time of reconstitution). * If refrigerated, allow the prepared IMDELLTRA infusion bag to come room temperature prior to administration, and complete the infusion within 8 hours (including preparation and infusion time). * Do not re-refrigerate prepared infusion bag.

)

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Imdelltra Prescribing Information

Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving IMDELLTRA. Initiate IMDELLTRA using the step-up dosing schedule to reduce the incidence and severity of CRS. Withhold IMDELLTRA until CRS resolves or permanently discontinue based on severity

[see

2.5 IMDELLTRA Dosage Modifications and Adverse Reaction Management

No dose reduction for IMDELLTRA is recommended. See Table 5and Table 6for recommended management of CRS, neurologic toxicity including ICANS respectively and Table 7 for cytopenias, infections and other adverse reactions.

Cytokine Release Syndrome (CRS)

Diagnose CRS based on clinical presentation

[see Warnings and Precautions (5.1)]

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

If CRS is suspected, manage according to the recommendations in Table 5. Monitor patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygen) with continuous cardiac telemetry and pulse oximetry.

For severe or life-threatening CRS, recommend administering tocilizumab or equivalent therapy and intensive monitoring (e.g., ICU) for supportive therapy. Perform laboratory testing to monitor for disseminated intravascular coagulation (DIC), hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function. Table 5 provides the guidelines for grading and dosage modification and management of cytokine release syndrome.

Table 5. Guidelines for Grading and Dosage Modification and Management of Cytokine Release SyndromeCRS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus

Grading (2019).
CRS Grade	Defining Symptoms	IMDELLTRA Dosage Modification	Management
Grade 1	Symptoms require symptomatic treatment only (e.g., fever ≥ 100.4°F without hypotension or hypoxia).	Withhold IMDELLTRA until event resolves, then resume IMDELLTRA at the next scheduled doseSee Table 4for recommendations on restarting IMDELLTRA after dose delays [see Dosage and Administration (2.4)] ..	Administer symptomatic treatment (e.g., acetaminophen) for fever. Consider dexamethasone 4 mg to 10 mg oral or IV (or equivalent)Taper steroids per standard of care guidelines..
Grade 2	Symptoms require and respond to moderate intervention. Fever ≥ 100.4°F, Hypotension responsive to fluids not requiring vasopressors and/or Hypoxia requiring low flow nasal cannula or blow-by.	Withhold IMDELLTRA until event resolves, then resume IMDELLTRA at the next scheduled dose .	Recommend hospitalization for a minimum of 24 hours with cardiac telemetry and pulse oximetry. Administer symptomatic treatment (e.g., acetaminophen) for fever. Administer supplemental oxygen and intravenous fluids when indicated. Consider dexamethasone (or equivalent) 8 mg oral or IV. Consider tocilizumab (or equivalent). When resuming the next planned dose, monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours in an appropriate healthcare setting .
Grade 3	Severe symptoms defined as temperature ≥ 100.4°F with: Hemodynamic instability requiring a vasopressor (with or without vasopressin) and/or Worsening hypoxia or respiratory distress requiring high flow nasal cannula (> 6 L/min oxygen) or face mask.	Withhold IMDELLTRA until the event resolves, then resume IMDELLTRA at the next scheduled dose . For recurrent Grade 3 events, permanently discontinue IMDELLTRA.	In addition to Grade 2 treatment: Recommend intensive monitoring, e.g., ICU care. Administer dexamethasone^c(or equivalent) 8 mg IV every 8 hours up to 3 doses. Vasopressor support as needed. High flow oxygen support as needed. Recommend tocilizumab (or equivalent). Prior to the next dose, administer concomitant medications as recommended for Cycle 1 Day 1 and Cycle 1 Day 8 (see Table 3). When resuming the next planned dose, monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours in an appropriate healthcare setting .
Grade 4	Life-threatening symptoms defined as temperature ≥ 100.4°F with: Hemodynamic instability requiring multiple vasopressors (excluding vasopressin). and/or Worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure.	Permanently discontinue IMDELLTRA.	ICU care. Per Grade 3 treatment. Recommend tocilizumab (or equivalent)

Neurologic Toxicity including ICANS

At the first sign of neurologic toxicity, including ICANS, withhold IMDELLTRA and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for severe or life-threatening neurologic toxicities, including ICANS

[see Warnings and Precautions (5.2)]

. Manage ICANS and neurologic toxicity according to the recommendations in Table 6 and consider further management per current practice guidelines.

Table 6. Guidelines for Management of Neurologic Toxicity including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)ICANS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (2019)
ICANS Grade	Defining Symptoms	IMDELLTRA Dosage Modifications	Management
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 pointswith no depressed level of consciousness.	Withhold IMDELLTRA until ICANS resolves, then resume IMDELLTRA at the next scheduled doseSee Table 4 for recommendations on restarting IMDELLTRA after dose delays [see Dosage and Administration (2.4)] .	Supportive care.
Grade 2	ICE score 3-6 and/or mild somnolence awaking to voice.	Withhold IMDELLTRA until ICANS resolves, then resume IMDELLTRA at the next scheduled dose .	Supportive care. DexamethasoneTaper steroids per standard of care guidelines(or equivalent) 8 to 10 mg oral or IV. Can repeat every 12 hours or methylprednisolone (or equivalent) 1 mg/kg IV every 12 hours if symptoms worsen. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours following the next dose of IMDELLTRA.
Grade 3	ICE score 0-2 and/or depressed level of consciousness awakening only to tactile stimulus and/or any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention and/or Focal or local edema on neuroimaging.	Withhold IMDELLTRA until the ICANS resolves, then resume IMDELLTRA at the next scheduled dose . If there is no improvement to Grade ≤ 1 within 7 days permanently discontinue IMDELLTRA. For recurrent Grade 3 events, permanently discontinue IMDELLTRA.	Recommend intensive monitoring, e.g., ICU care. Consider mechanical ventilation for airway protection. Dexamethasone (or equivalent) 10 mg IV every 6 hours or methylprednisolone (or equivalent) 1 mg/kg IV every 12 hours. Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent Grade ≥ 3 neurotoxicity. Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours following the next dose of IMDELLTRA.
Grade 4	ICE score 0 (patient is unarousable and unable to perform ICE) and/or Stupor or coma and/or Life-threatening prolonged seizure (> 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between and/or diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing or papilledema, cranial nerve VI palsy, or Cushing's triad.	Permanently discontinue IMDELLTRA.	ICU care. Consider mechanical ventilation for airway protection. High dose corticosteroids (e.g., methylprednisolone 1000 mg/day in divided doses IV for 3 days). Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent Grade ≥ 3 neurotoxicity. Treat convulsive status epilepticus per institutional guidelines.

Table 7. Recommended Treatment Interruptions of IMDELLTRA for the Management of Cytopenias, Infections, and Other Adverse Reactions
Adverse Reactions	SeveritySeverity based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.	Dosage ModificationRefer to Table 4 for dose restarting guidance.
Cytopenias [see Warnings and Precautions (5.3)]	Grade 3 Neutropenia	Withhold IMDELLTRA until recovery to Grade ≤ 2. Consider administration of granulocyte colony stimulating factor (G-CSF). Permanently discontinue if recovery to Grade ≤ 2 does not occur within 3 weeks.
	Grade 4 Neutropenia	Withhold IMDELLTRA until recovery to Grade ≤ 2. Consider administration of granulocyte colony stimulating factor (G-CSF). Permanently discontinue if recovery to Grade ≤ 2 does not occur within 1 week.
	Recurrent Grade 4 Neutropenia	Permanently discontinue IMDELLTRA
	Febrile neutropenia	Withhold IMDELLTRA until neutropenia recovers to Grade ≤ 2 and fever resolves.
	Hemoglobin <8 g/dL	Withhold IMDELLTRA until hemoglobin is ≥8 g/dL.
	Grade 3 or Grade 4 Decreased platelet count	Withhold IMDELLTRA until platelet count is Grade ≤ 2 and no evidence of bleeding. Permanently discontinue if recovery to Grade ≤ 2 does not occur within 3 weeks.
	Recurrent Grade 4 Decreased platelet count	Permanently discontinue IMDELLTRA.
Infections [see Warnings and Precautions (5.4)]	All Grades	Withhold IMDELLTRA in the step-up phase in patients until infection resolves.
	Grade 3	Withhold IMDELLTRA during the treatment phase until infection improves to Grade ≤ 1 .
	Grade 4	Permanently discontinue IMDELLTRA.
Hepatotoxicity [see Warnings and Precautions (5.5)]	Grade 3 Increased ALT or AST or bilirubin	Withhold IMDELLTRA until improved to Grade ≤ 1.
	Grade 4 Increased ALT or AST or bilirubin	Permanently discontinue IMDELLTRA.
	AST or ALT > 3 × ULN with total bilirubin > 2 × ULN in the absence of alternative causes	Permanently discontinue IMDELLTRA.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3 or 4	Withhold IMDELLTRA until recovery to Grade ≤ 1 or baseline. Consider permanently discontinuing if adverse reaction does not resolve within 28 days. Consider permanent discontinuation for Grade 4 events.

and

5.1 Cytokine Release Syndrome

IMDELLTRA can cause cytokine release syndrome (CRS) including life-threatening or fatal reactions.

In the pooled safety population

[see Adverse Reactions (6.1)]

, CRS occurred in 57% (268/473) of patients who received IMDELLTRA, including 39% Grade 1, 15% Grade 2, 1.7% Grade 3 and 0.2% Grade 4. Recurrent CRS occurred in 24% of IMDELLTRA-treated patients including 20% Grade 1 and 3.4% Grade 2; one patient experienced recurrent Grade 3.

Among the 268 patients who experienced CRS, 73% had CRS after the first dose, 60% had CRS after the second dose, and 15% had CRS following the third or later dose. Following the Cycle 1 Day 1, Day 8, Day 15 infusions, 24%, 8%, and 1% of patients experienced Grade ≥ 2 CRS, respectively. From Cycle 2 onwards, 1.5% of patients experienced Grade ≥ 2 CRS. Of the patients who experienced CRS, 31% received steroids and 10% required tocilizumab. The median time to onset of all grade CRS from most recent dose of IMDELLTRA was 16 hours (range: start of infusion to 15 days). The median time to onset of Grade ≥ 2 CRS from most recent dose of IMDELLTRA was 15 hours (range: start of infusion to 15 days).

Clinical signs and symptoms of CRS included pyrexia, hypotension, fatigue, tachycardia, headache, hypoxia, nausea and vomiting. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

Administer IMDELLTRA following the recommended step-up dosing and administer concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3 to reduce the risk of CRS

[see Dosage and Administration (2.3)]

. Administer IMDELLTRA in an appropriate healthcare facility equipped to monitor and manage CRS. Ensure patients are well hydrated prior to administration of IMDELLTRA.

Closely monitor patients for signs and symptoms of CRS during treatment with IMDELLTRA. At the first sign of CRS, immediately discontinue IMDELLTRA infusion, evaluate the patient for hospitalization and institute supportive care based on severity. Withhold or permanently discontinue IMDELLTRA based on severity

[see Dosage and Administration (2.5)]

. Counsel patients and caregivers to seek medical attention should signs or symptoms of CRS occur.

]

Neurologic toxicity and immune effector cell-associated neurotoxicity syndrome (ICANS), including life-threatening or fatal reactions, can occur in patients receiving IMDELLTRA. Monitor patients for signs and symptoms of neurologic toxicity, including ICANS, during treatment and treat promptly. Withhold IMDELLTRA until ICANS resolves or permanently discontinue based on severity

[see

2.5 IMDELLTRA Dosage Modifications and Adverse Reaction Management

Cytokine Release Syndrome (CRS)

Diagnose CRS based on clinical presentation

[see Warnings and Precautions (5.1)]

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

Table 5. Guidelines for Grading and Dosage Modification and Management of Cytokine Release SyndromeCRS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus

Grading (2019).
CRS Grade	Defining Symptoms	IMDELLTRA Dosage Modification	Management
Grade 1	Symptoms require symptomatic treatment only (e.g., fever ≥ 100.4°F without hypotension or hypoxia).	Withhold IMDELLTRA until event resolves, then resume IMDELLTRA at the next scheduled doseSee Table 4for recommendations on restarting IMDELLTRA after dose delays [see Dosage and Administration (2.4)] ..	Administer symptomatic treatment (e.g., acetaminophen) for fever. Consider dexamethasone 4 mg to 10 mg oral or IV (or equivalent)Taper steroids per standard of care guidelines..
Grade 2	Symptoms require and respond to moderate intervention. Fever ≥ 100.4°F, Hypotension responsive to fluids not requiring vasopressors and/or Hypoxia requiring low flow nasal cannula or blow-by.	Withhold IMDELLTRA until event resolves, then resume IMDELLTRA at the next scheduled dose .	Recommend hospitalization for a minimum of 24 hours with cardiac telemetry and pulse oximetry. Administer symptomatic treatment (e.g., acetaminophen) for fever. Administer supplemental oxygen and intravenous fluids when indicated. Consider dexamethasone (or equivalent) 8 mg oral or IV. Consider tocilizumab (or equivalent). When resuming the next planned dose, monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours in an appropriate healthcare setting .
Grade 3	Severe symptoms defined as temperature ≥ 100.4°F with: Hemodynamic instability requiring a vasopressor (with or without vasopressin) and/or Worsening hypoxia or respiratory distress requiring high flow nasal cannula (> 6 L/min oxygen) or face mask.	Withhold IMDELLTRA until the event resolves, then resume IMDELLTRA at the next scheduled dose . For recurrent Grade 3 events, permanently discontinue IMDELLTRA.	In addition to Grade 2 treatment: Recommend intensive monitoring, e.g., ICU care. Administer dexamethasone^c(or equivalent) 8 mg IV every 8 hours up to 3 doses. Vasopressor support as needed. High flow oxygen support as needed. Recommend tocilizumab (or equivalent). Prior to the next dose, administer concomitant medications as recommended for Cycle 1 Day 1 and Cycle 1 Day 8 (see Table 3). When resuming the next planned dose, monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours in an appropriate healthcare setting .
Grade 4	Life-threatening symptoms defined as temperature ≥ 100.4°F with: Hemodynamic instability requiring multiple vasopressors (excluding vasopressin). and/or Worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure.	Permanently discontinue IMDELLTRA.	ICU care. Per Grade 3 treatment. Recommend tocilizumab (or equivalent)

Neurologic Toxicity including ICANS

[see Warnings and Precautions (5.2)]

. Manage ICANS and neurologic toxicity according to the recommendations in Table 6 and consider further management per current practice guidelines.

Table 6. Guidelines for Management of Neurologic Toxicity including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)ICANS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (2019)
ICANS Grade	Defining Symptoms	IMDELLTRA Dosage Modifications	Management
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 pointswith no depressed level of consciousness.	Withhold IMDELLTRA until ICANS resolves, then resume IMDELLTRA at the next scheduled doseSee Table 4 for recommendations on restarting IMDELLTRA after dose delays [see Dosage and Administration (2.4)] .	Supportive care.
Grade 2	ICE score 3-6 and/or mild somnolence awaking to voice.	Withhold IMDELLTRA until ICANS resolves, then resume IMDELLTRA at the next scheduled dose .	Supportive care. DexamethasoneTaper steroids per standard of care guidelines(or equivalent) 8 to 10 mg oral or IV. Can repeat every 12 hours or methylprednisolone (or equivalent) 1 mg/kg IV every 12 hours if symptoms worsen. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours following the next dose of IMDELLTRA.
Grade 3	ICE score 0-2 and/or depressed level of consciousness awakening only to tactile stimulus and/or any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention and/or Focal or local edema on neuroimaging.	Withhold IMDELLTRA until the ICANS resolves, then resume IMDELLTRA at the next scheduled dose . If there is no improvement to Grade ≤ 1 within 7 days permanently discontinue IMDELLTRA. For recurrent Grade 3 events, permanently discontinue IMDELLTRA.	Recommend intensive monitoring, e.g., ICU care. Consider mechanical ventilation for airway protection. Dexamethasone (or equivalent) 10 mg IV every 6 hours or methylprednisolone (or equivalent) 1 mg/kg IV every 12 hours. Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent Grade ≥ 3 neurotoxicity. Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours following the next dose of IMDELLTRA.
Grade 4	ICE score 0 (patient is unarousable and unable to perform ICE) and/or Stupor or coma and/or Life-threatening prolonged seizure (> 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between and/or diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing or papilledema, cranial nerve VI palsy, or Cushing's triad.	Permanently discontinue IMDELLTRA.	ICU care. Consider mechanical ventilation for airway protection. High dose corticosteroids (e.g., methylprednisolone 1000 mg/day in divided doses IV for 3 days). Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent Grade ≥ 3 neurotoxicity. Treat convulsive status epilepticus per institutional guidelines.

Table 7. Recommended Treatment Interruptions of IMDELLTRA for the Management of Cytopenias, Infections, and Other Adverse Reactions
Adverse Reactions	SeveritySeverity based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.	Dosage ModificationRefer to Table 4 for dose restarting guidance.
Cytopenias [see Warnings and Precautions (5.3)]	Grade 3 Neutropenia	Withhold IMDELLTRA until recovery to Grade ≤ 2. Consider administration of granulocyte colony stimulating factor (G-CSF). Permanently discontinue if recovery to Grade ≤ 2 does not occur within 3 weeks.
	Grade 4 Neutropenia	Withhold IMDELLTRA until recovery to Grade ≤ 2. Consider administration of granulocyte colony stimulating factor (G-CSF). Permanently discontinue if recovery to Grade ≤ 2 does not occur within 1 week.
	Recurrent Grade 4 Neutropenia	Permanently discontinue IMDELLTRA
	Febrile neutropenia	Withhold IMDELLTRA until neutropenia recovers to Grade ≤ 2 and fever resolves.
	Hemoglobin <8 g/dL	Withhold IMDELLTRA until hemoglobin is ≥8 g/dL.
	Grade 3 or Grade 4 Decreased platelet count	Withhold IMDELLTRA until platelet count is Grade ≤ 2 and no evidence of bleeding. Permanently discontinue if recovery to Grade ≤ 2 does not occur within 3 weeks.
	Recurrent Grade 4 Decreased platelet count	Permanently discontinue IMDELLTRA.
Infections [see Warnings and Precautions (5.4)]	All Grades	Withhold IMDELLTRA in the step-up phase in patients until infection resolves.
	Grade 3	Withhold IMDELLTRA during the treatment phase until infection improves to Grade ≤ 1 .
	Grade 4	Permanently discontinue IMDELLTRA.
Hepatotoxicity [see Warnings and Precautions (5.5)]	Grade 3 Increased ALT or AST or bilirubin	Withhold IMDELLTRA until improved to Grade ≤ 1.
	Grade 4 Increased ALT or AST or bilirubin	Permanently discontinue IMDELLTRA.
	AST or ALT > 3 × ULN with total bilirubin > 2 × ULN in the absence of alternative causes	Permanently discontinue IMDELLTRA.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3 or 4	Withhold IMDELLTRA until recovery to Grade ≤ 1 or baseline. Consider permanently discontinuing if adverse reaction does not resolve within 28 days. Consider permanent discontinuation for Grade 4 events.

and

5.2 Neurologic Toxicity Including ICANS

IMDELLTRA can cause life-threatening or fatal neurologic toxicity including ICANS.

In the pooled safety population

[see Adverse Reactions (6.1)]

, neurologic toxicity occurred in 65% of patients who received IMDELLTRA, with Grade 3 or higher events in 7% of patients including fatal events in 0.2%. The most frequent neurologic toxicities were dysgeusia (34%), headache (17%), peripheral neuropathy (9%), dizziness (9%), and insomnia (8%).

The incidence of signs and symptoms consistent with ICANS was 10% in IMDELLTRA- treated patients, including events with the preferred terms: ICANs (4.7%), muscular weakness (3.2%), cognitive disorder (0.6%), aphasia (0.6%), depressed level of consciousness (0.4%), seizures (0.4%), encephalopathy (0.4%), and leukoencephalopathy (0.2%). There was one fatal reaction of ICANS

[see Adverse Reactions (6.1)]

. Recurrent ICANS occurred in 1.5% of patients. Of the patients who experienced ICANS, most experienced the event following Cycle 1 Day 1 (2.5%) and Cycle 1 Day 8 (3.6%). Following Day 1, Day 8, and Day 15 infusions, 1.3%, 1.3% and 0.4% of patients experienced Grade ≥ 2 ICANS, respectively. ICANS can occur several weeks following administration of IMDELLTRA. The median time to onset of ICANS from the first dose of IMDELLTRA was 16 days (range: 1 to 862 days). The median time to resolution of ICANS was 4 days (range: 1 to 40 days).

The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

Patients receiving IMDELLTRA are at risk of neurologic adverse reactions and ICANS resulting in depressed level of consciousness. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until neurologic symptoms resolve

Closely monitor patients for signs and symptoms of neurologic toxicity and ICANS during treatment with IMDELLTRA. At the first sign of ICANS, immediately discontinue the infusion, evaluate the patient and provide supportive therapy based on severity.

Withhold IMDELLTRA or permanently discontinue based on severity

[see Dosage and Administration (2.5)]

]

Indications and Usage (

1 INDICATIONS AND USAGE

IMDELLTRA is indicated for the treatment of adult patients with extensive stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy.

IMDELLTRA is a bispecific delta-like ligand 3 (DLL3)-directed CD3 T- cell engager indicated for the treatment of adult patients with extensive stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum

based chemotherapy.

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Dosage and Administration (

2.1 Important Dosage and Administration Information

Administer IMDELLTRA according to the step-up dose and schedule in Table 1 to reduce the incidence and severity of cytokine release syndrome (CRS)
[see Dosage and Administration (2.2)]
.
Evaluate complete blood count, liver enzymes and bilirubin prior to administration of all doses of IMDELLTRA up through Cycle 5 Day 15 and then prior to administration of IMDELLTRA on Day 1 of each cycle starting with Cycle 6. More frequent evaluation may be necessary if clinically indicated
[see Warnings and Precautions (5.3, 5.5)]
.
Ensure patients are well hydrated prior to administration of IMDELLTRA
[see Warnings and Precautions (5.1)]
.
For Cycle 1, administer recommended concomitant medications in Table 3 before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions to reduce the risk of CRS reactions
[see Dosage and Administration (2.3)]
.
IMDELLTRA should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions, such as CRS and neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS)
[see Warnings and Precautions (5.1, 5.2)]
.
Due to the risk of CRS and neurologic toxicity, including ICANS, monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting
[see Dosage and Administration (2.5)and Warnings and Precautions (5.1, 5.2)]
.
Recommend patients to remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the infusion with IMDELLTRA following Cycle 1 Day 1 and Cycle 1 Day 8 doses, accompanied by a caregiver.
Inform both the patient and the caregiver on the signs and symptoms of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) prior to discharge.

2.2 Recommended Dosage and Administration

Administer IMDELLTRA as an intravenous infusion for one hour.
The recommended step-up dose and schedule for IMDELLTRA is provided in Table 1. Administer step-up dose and schedule on Cycle 1 Day 1 to reduce the incidence and severity of CRS.
After step-up dose and schedule on Cycle 1 Day 1, administer IMDELLTRA every 2 weeks until disease progression or unacceptable toxicity.

Table 1. Recommended Dose and Schedule of IMDELLTRA
Dosing Schedule	Day	Dose of IMDELLTRA	Administration Instructions	Recommended Monitoring
Note: See Table 4for recommendation on restarting IMDELLTRA after dose delays.
Step-up Dose and Schedule Cycle 1	Day 1Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3.	Step-up dose 1 mg	Administer IMDELLTRA as a 1-hour intravenous infusion in an appropriate healthcare setting.	Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the IMDELLTRA infusion accompanied by a caregiver.
	Day 8	10 mg
	Day 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusionExtended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥ 2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5and 6for monitoring recommendations.
Cycle 2	Day 1 and 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion .
Cycles 3 and 4	Day 1 and 15	10 mg		Observe patients for 3-4 hours post IMDELLTRA infusion .
Cycle 5 and subsequent infusions	Day 1 and 15	10 mg		Observe patients for 2 hours post IMDELLTRA infusion .

Administration

The intravenous (IV) catheter for concomitant medications administration can be used to administer the IMDELLTRA infusion.
To ensure patency, flush the IV catheter over 3 to 5 minutes using 0.9% Sodium Chloride for Injection.
Administer the reconstituted and diluted IMDELLTRA as a 1-hour intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. Flush the IV-line upon completion of the IMDELLTRA infusion.

Table 2 provides the infusion duration and rate.

Table 2. IMDELLTRA Infusion Duration and Rate
Infusion Duration for 250 mL IV Preparation	Infusion Rate
1 hour	250 mL/hour

2.3 Recommended Concomitant Medications for IMDELLTRA Administration for Cycle 1 Day 1 and Cycle 1 Day 8

Administer recommended concomitant medications for IMDELLTRA during Cycle 1 Day 1 and Cycle 1 Day 8 as presented in Table 3 to reduce the risk of CRS

[see Warnings and Precautions (5.1)]

Table 3. Recommended Concomitant Medications for IMDELLTRA Administration for Cycle 1 Day 1 and Cycle 1 Day 8
Treatment Day	Medication	Administration
Cycle 1 Day 1 and Cycle 1 Day 8	Administer dexamethasone 8 mg intravenously (or equivalent)	Within 1 hour prior to IMDELLTRA administration
Cycle 1 Day 1 and Cycle 1 Day 8	Administer 1 liter of normal saline intravenously over 2 to 4 hours	Immediately after completion of IMDELLTRA infusion

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Dosage and Administration (

2.4 Restarting IMDELLTRA After Dosage Delay

If a dose of IMDELLTRA is delayed, restart based on the recommendation as listed in Table 4 and resume the dose and schedule accordingly

[see Dosage and Administration (2.2)]

Administer recommended concomitant medications as indicated in Table 3.

Table 4. Recommendations for Restarting IMDELLTRA After Dosage Delay
Last Dose Administered	Time Since the Last Dose Administered	ActionAdminister recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions and monitor patients accordingly [see Dosage and Administration (2.1, 2.2and 2.3)] .
1 mg on Cycle 1 Day 1	2 weeks or less (≤ 14 days)	Administer IMDELLTRA 10 mg, then resume with the planned dose and schedule.
1 mg on Cycle 1 Day 1	Greater than 2 weeks (> 14 days)	Administer IMDELLTRA step-up dose 1 mg. If tolerated, increase to 10 mg 1 week later. Then resume with the planned dose and schedule.
10 mg on Cycle 1 Day 8	3 weeks or less (≤ 21 days)	Administer IMDELLTRA 10 mg, then resume with the planned dose and schedule.
10 mg on Cycle 1 Day 8	Greater than 3 weeks (> 21 days)	Administer IMDELLTRA step-up dose 1 mg. If tolerated, increase to 10 mg 1 week later. Then resume with the planned dose and schedule.
10 mg on Cycle 1 Day 15 and subsequent Cycles every 2 weeks thereafter	4 weeks or less (≤ 28 days)	Administer IMDELLTRA 10 mg, then resume with the planned dose and schedule.
	Greater than 4 weeks (> 28 days)	Administer IMDELLTRA step-up dose 1 mg. If tolerated, increase to 10 mg 1 week later. Then resume with the planned dose and schedule.

2.5 IMDELLTRA Dosage Modifications and Adverse Reaction Management

Cytokine Release Syndrome (CRS)

Diagnose CRS based on clinical presentation

[see Warnings and Precautions (5.1)]

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

Table 5. Guidelines for Grading and Dosage Modification and Management of Cytokine Release SyndromeCRS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus

Grading (2019).
CRS Grade	Defining Symptoms	IMDELLTRA Dosage Modification	Management
Grade 1	Symptoms require symptomatic treatment only (e.g., fever ≥ 100.4°F without hypotension or hypoxia).	Withhold IMDELLTRA until event resolves, then resume IMDELLTRA at the next scheduled doseSee Table 4for recommendations on restarting IMDELLTRA after dose delays [see Dosage and Administration (2.4)] ..	Administer symptomatic treatment (e.g., acetaminophen) for fever. Consider dexamethasone 4 mg to 10 mg oral or IV (or equivalent)Taper steroids per standard of care guidelines..
Grade 2	Symptoms require and respond to moderate intervention. Fever ≥ 100.4°F, Hypotension responsive to fluids not requiring vasopressors and/or Hypoxia requiring low flow nasal cannula or blow-by.	Withhold IMDELLTRA until event resolves, then resume IMDELLTRA at the next scheduled dose .	Recommend hospitalization for a minimum of 24 hours with cardiac telemetry and pulse oximetry. Administer symptomatic treatment (e.g., acetaminophen) for fever. Administer supplemental oxygen and intravenous fluids when indicated. Consider dexamethasone (or equivalent) 8 mg oral or IV. Consider tocilizumab (or equivalent). When resuming the next planned dose, monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours in an appropriate healthcare setting .
Grade 3	Severe symptoms defined as temperature ≥ 100.4°F with: Hemodynamic instability requiring a vasopressor (with or without vasopressin) and/or Worsening hypoxia or respiratory distress requiring high flow nasal cannula (> 6 L/min oxygen) or face mask.	Withhold IMDELLTRA until the event resolves, then resume IMDELLTRA at the next scheduled dose . For recurrent Grade 3 events, permanently discontinue IMDELLTRA.	In addition to Grade 2 treatment: Recommend intensive monitoring, e.g., ICU care. Administer dexamethasone^c(or equivalent) 8 mg IV every 8 hours up to 3 doses. Vasopressor support as needed. High flow oxygen support as needed. Recommend tocilizumab (or equivalent). Prior to the next dose, administer concomitant medications as recommended for Cycle 1 Day 1 and Cycle 1 Day 8 (see Table 3). When resuming the next planned dose, monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours in an appropriate healthcare setting .
Grade 4	Life-threatening symptoms defined as temperature ≥ 100.4°F with: Hemodynamic instability requiring multiple vasopressors (excluding vasopressin). and/or Worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure.	Permanently discontinue IMDELLTRA.	ICU care. Per Grade 3 treatment. Recommend tocilizumab (or equivalent)

Neurologic Toxicity including ICANS

[see Warnings and Precautions (5.2)]

. Manage ICANS and neurologic toxicity according to the recommendations in Table 6 and consider further management per current practice guidelines.

Table 6. Guidelines for Management of Neurologic Toxicity including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)ICANS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (2019)
ICANS Grade	Defining Symptoms	IMDELLTRA Dosage Modifications	Management
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 pointswith no depressed level of consciousness.	Withhold IMDELLTRA until ICANS resolves, then resume IMDELLTRA at the next scheduled doseSee Table 4 for recommendations on restarting IMDELLTRA after dose delays [see Dosage and Administration (2.4)] .	Supportive care.
Grade 2	ICE score 3-6 and/or mild somnolence awaking to voice.	Withhold IMDELLTRA until ICANS resolves, then resume IMDELLTRA at the next scheduled dose .	Supportive care. DexamethasoneTaper steroids per standard of care guidelines(or equivalent) 8 to 10 mg oral or IV. Can repeat every 12 hours or methylprednisolone (or equivalent) 1 mg/kg IV every 12 hours if symptoms worsen. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours following the next dose of IMDELLTRA.
Grade 3	ICE score 0-2 and/or depressed level of consciousness awakening only to tactile stimulus and/or any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention and/or Focal or local edema on neuroimaging.	Withhold IMDELLTRA until the ICANS resolves, then resume IMDELLTRA at the next scheduled dose . If there is no improvement to Grade ≤ 1 within 7 days permanently discontinue IMDELLTRA. For recurrent Grade 3 events, permanently discontinue IMDELLTRA.	Recommend intensive monitoring, e.g., ICU care. Consider mechanical ventilation for airway protection. Dexamethasone (or equivalent) 10 mg IV every 6 hours or methylprednisolone (or equivalent) 1 mg/kg IV every 12 hours. Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent Grade ≥ 3 neurotoxicity. Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours following the next dose of IMDELLTRA.
Grade 4	ICE score 0 (patient is unarousable and unable to perform ICE) and/or Stupor or coma and/or Life-threatening prolonged seizure (> 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between and/or diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing or papilledema, cranial nerve VI palsy, or Cushing's triad.	Permanently discontinue IMDELLTRA.	ICU care. Consider mechanical ventilation for airway protection. High dose corticosteroids (e.g., methylprednisolone 1000 mg/day in divided doses IV for 3 days). Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent Grade ≥ 3 neurotoxicity. Treat convulsive status epilepticus per institutional guidelines.

Table 7. Recommended Treatment Interruptions of IMDELLTRA for the Management of Cytopenias, Infections, and Other Adverse Reactions
Adverse Reactions	SeveritySeverity based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.	Dosage ModificationRefer to Table 4 for dose restarting guidance.
Cytopenias [see Warnings and Precautions (5.3)]	Grade 3 Neutropenia	Withhold IMDELLTRA until recovery to Grade ≤ 2. Consider administration of granulocyte colony stimulating factor (G-CSF). Permanently discontinue if recovery to Grade ≤ 2 does not occur within 3 weeks.
	Grade 4 Neutropenia	Withhold IMDELLTRA until recovery to Grade ≤ 2. Consider administration of granulocyte colony stimulating factor (G-CSF). Permanently discontinue if recovery to Grade ≤ 2 does not occur within 1 week.
	Recurrent Grade 4 Neutropenia	Permanently discontinue IMDELLTRA
	Febrile neutropenia	Withhold IMDELLTRA until neutropenia recovers to Grade ≤ 2 and fever resolves.
	Hemoglobin <8 g/dL	Withhold IMDELLTRA until hemoglobin is ≥8 g/dL.
	Grade 3 or Grade 4 Decreased platelet count	Withhold IMDELLTRA until platelet count is Grade ≤ 2 and no evidence of bleeding. Permanently discontinue if recovery to Grade ≤ 2 does not occur within 3 weeks.
	Recurrent Grade 4 Decreased platelet count	Permanently discontinue IMDELLTRA.
Infections [see Warnings and Precautions (5.4)]	All Grades	Withhold IMDELLTRA in the step-up phase in patients until infection resolves.
	Grade 3	Withhold IMDELLTRA during the treatment phase until infection improves to Grade ≤ 1 .
	Grade 4	Permanently discontinue IMDELLTRA.
Hepatotoxicity [see Warnings and Precautions (5.5)]	Grade 3 Increased ALT or AST or bilirubin	Withhold IMDELLTRA until improved to Grade ≤ 1.
	Grade 4 Increased ALT or AST or bilirubin	Permanently discontinue IMDELLTRA.
	AST or ALT > 3 × ULN with total bilirubin > 2 × ULN in the absence of alternative causes	Permanently discontinue IMDELLTRA.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3 or 4	Withhold IMDELLTRA until recovery to Grade ≤ 1 or baseline. Consider permanently discontinuing if adverse reaction does not resolve within 28 days. Consider permanent discontinuation for Grade 4 events.

2.6 Preparation

Material Compatibility Information

IV bags composed of ethyl vinyl acetate (EVA), polyolefin, and polyvinyl chloride (PVC) have been shown to be compatible with IMDELLTRA at the specified administration conditions.
IV line and catheter materials composed of polyolefin, PVC, and polyurethane have been shown to be compatible with IMDELLTRA at the specified administration conditions.
The use of Closed System Transfer Device (CSTD) is not recommended due to potential wrong dose medication error risk. Amgen has not performed compatibility testing of vial adaptor CSTDs with IMDELLTRA.

Step 1: Reconstitute IMDELLTRA with Sterile Water for Injection

Table 8 provides the required amount of sterile water for injection required to reconstitute IMDELLTRA 1 mg and 10 mg vials.

Do not

use IV Solution Stabilizer (IVSS) to reconstitute IMDELLTRA

The IV Solution Stabilizer (IVSS) is used to coat the intravenous bag prior to addition of reconstituted IMDELLTRA to prevent adsorption of IMDELLTRA to IV bags and IV tubing.

Table 8. Required Amount of Sterile Water for Injection to Reconstitute IMDELLTRAEach vial contains overfill to allow for withdrawal of 1.1 mL (1 mg vial) or 4.2 mL (10 mg vial) after reconstitution to ensure delivery at the stated concentration of labeled vial strength.
IMDELLTRA Vial Strength	Amount of Sterile Water for Injection Needed to Reconstitute IMDELLTRA	Resulting Concentration
1 mg	1.3 mL	0.9 mg/mL
10 mg	4.4 mL	2.4 mg/mL

Using a needle and syringe filled with the required amount of sterile water, inject the sterile water against the glass vial. Avoid injecting the water directly onto the powder to prevent foaming.
Gently swirl the contents to mix. Do not shake.
Inspect parenteral drug products for particulate matter and discoloration prior to administration. Inspect that the solution is clear to opalescent, colorless to slightly yellow. Do not use if the solution is cloudy or has particulates.
Further dilute reconstituted IMDELLTRA.
The reconstituted IMDELLTRA must be further diluted within 4 hours of reconstitution or discarded.

Prepare the infusion bag: Steps 2 to 5

Step 2 : Withdraw 0.9% Sodium Chloride for Injection

Using a 250 mL prefilled bag of 0.9% Sodium Chloride for Injection, withdraw the amount of sodium chloride specified in Table 9 and discard.

Table 9. Required Amount of 0.9% Sodium Chloride to Withdraw from 250 mL IV Bag
IMDELLTRA Vial Strength	IMDELLTRA Dose	Volume of 0.9% Sodium Chloride to Withdraw From 250 mL IV Bag
1 mg	1 mg	14 mL
10 mg	10 mg	17 mL

Step 3: Add IV Solution Stabilizer to the infusion bag

Inject 13 mL of IV Solution Stabilizer (IVSS) into the 250 mL 0.9% Sodium Chloride infusion bag
,
see Table 10
.
Gently mix the contents of the infusion bag to avoid foaming. Do not shake.

Table 10. Required Amount of IV Solution Stabilizer (IVSS) to Add to IV Bag
IMDELLTRA Vial Strength	IMDELLTRA Dose	Volume of IV Solution Stabilizer (IVSS) to Add to IV Bag
1 mg	1 mg	13 mL
10 mg	10 mg	13 mL

Step 4: Dilute the reconstituted IMDELLTRA into the infusion bag

Transfer the required volume of reconstituted IMDELLTRA listed in Table 11 to the infusion bag
(containing IV Solution Stabilizer)
.

NOTE: The final concentrations for the different strength vials are NOT the same following reconstitution and further dilution.

Table 11. Required Amount of Reconstituted IMDELLTRA to Add to 250 mL IV Bag
IMDELLTRA Vial Strength	IMDELLTRA Dose	Volume of Reconstituted IMDELLTRA to Add to 250 mL IV Bag
1 mg	1 mg	1.1 mL
10 mg	10 mg	4.2 mL

Gently mix the contents of the bag. Do not shake.

Step 5: Remove air from IV bag

Remove air from the prepared IV bag using an empty syringe to avoid foaming.

Step 6: Prime IV tubing

Prime intravenous tubing with either 0.9% Sodium Chloride for Injection or with the final prepared product.
See Table 12for maximum storage time of prepared IMDELLTRA infusion.

Prepared IMDELLTRA Infusion Bag Storage Requirements

Administer reconstituted and diluted IMDELLTRA immediately.
Table 12 displays the maximum storage time for the prepared IMDELLTRA infusion bag.
Maximum storage time includes total duration from the time of reconstitution of the vial of IMDELLTRA to the end of the infusion.

Table 12. Maximum Storage Time for Prepared IMDELLTRA Infusion Bag
	Room Temperature 20°C to 25°C (68°F to 77°F)	Refrigerated 2°C to 8°C (36°F to 46°F)
Prepared IMDELLTRA Infusion Bag	8 hours	7 days
Discard the prepared IMDELLTRA infusion bag after maximum storage time (from time of reconstitution). If refrigerated, allow the prepared IMDELLTRA infusion bag to come room temperature prior to administration, and complete the infusion within 8 hours (including preparation and infusion time). Do not re-refrigerate prepared infusion bag.

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Warnings and Precautions (

5.1 Cytokine Release Syndrome

IMDELLTRA can cause cytokine release syndrome (CRS) including life-threatening or fatal reactions.

In the pooled safety population

[see Adverse Reactions (6.1)]

[see Dosage and Administration (2.3)]

. Administer IMDELLTRA in an appropriate healthcare facility equipped to monitor and manage CRS. Ensure patients are well hydrated prior to administration of IMDELLTRA.

[see Dosage and Administration (2.5)]

. Counsel patients and caregivers to seek medical attention should signs or symptoms of CRS occur.

5.2 Neurologic Toxicity Including ICANS

IMDELLTRA can cause life-threatening or fatal neurologic toxicity including ICANS.

In the pooled safety population

[see Adverse Reactions (6.1)]

Withhold IMDELLTRA or permanently discontinue based on severity

[see Dosage and Administration (2.5)]

5.3 Cytopenias

IMDELLTRA can cause cytopenias including neutropenia, thrombocytopenia, and anemia.

In the pooled safety population,

[see Adverse Reactions (6.1)]

based on laboratory data, decreased neutrophils occurred in 16% of patients, including 9% Grade 3 or 4. The median time to onset for Grade 3 or 4 decreased neutrophil count was 41 days (range: 2 to 306 days). Decreased platelets occurred in 30%, including 2.2% Grade 3 or 4. The median time to onset for Grade 3 or 4 decreased platelets was 67 days (range: 3 to 420 days). Decreased hemoglobin occurred in 56% of patients, including 4.7% Grade 3 or 4.

Febrile neutropenia was reported as an adverse event in 1.5% of patients treated with IMDELLTRA.

Monitor patients for signs and symptoms of cytopenias. Perform complete blood counts prior to treatment with all doses of IMDELLTRA, up through Cycle 5 Day 15 and then prior to administration of IMDELLTRA on Day 1 of each cycle starting with Cycle 6.

Based on the severity of cytopenias, temporarily withhold or permanently discontinue IMDELLTRA

[see Dosage and Administration (2.5)]

5.4 Infections

IMDELLTRA can cause serious infections, including life-threatening and fatal infections.

In the pooled safety population,

[see Adverse Reactions (6.1)]

, infections including opportunistic infections occurred in 43% of patients who received IMDELLTRA, including 14% Grade 3 or 4. The most frequent infections were pneumonia (11%), urinary tract infection (9%), COVID-19 (6%), upper respiratory tract infection (4.7%), respiratory tract infection (4%), candida infection (2.1%), oral candidiasis (2.1%) and nasopharyngitis (2.1%).

Monitor patients for signs and symptoms of infection prior to and during treatment with IMDELLTRA and treat as clinically indicated. Withhold or permanently discontinue IMDELLTRA based on severity

[see Dosage and Administration (2.5)]

)

11/2025

Warnings and Precautions, (

5.5 Hepatotoxicity

IMDELLTRA can cause hepatotoxicity.

In the pooled safety population

[see Adverse Reactions (6.1)]

, based on laboratory data, elevated ALT occurred in 39% of patients who received IMDELLTRA, including 2.5% Grade 3 or 4 ALT. Elevated AST occurred in 43% of patients, including 3.2% Grade 3 or 4. Elevated bilirubin occurred in 16% of patients, including 1.3% Grade 3 or 4

[see Adverse Reactions (6.1)]

. Liver enzyme elevation can occur with or without concurrent CRS.

Monitor liver enzymes and bilirubin prior to treatment with IMDELLTRA, and as clinically indicated. Withhold IMDELLTRA or permanently discontinue based on severity

[see Dosage and Administration (2.5)]

5.6 Hypersensitivity

IMDELLTRA can cause severe hypersensitivity reactions.

Clinical signs and symptoms of hypersensitivity may include, but are not limited to, rash and bronchospasm.

Monitor patients for signs and symptoms of hypersensitivity during treatment with IMDELLTRA and manage as clinically indicated. Withhold or consider permanent discontinuation of IMDELLTRA based on severity

[see Dosage and Administration (2.5)]

5.7 Embryo-Fetal Toxicity

Based on its mechanism of action, IMDELLTRA may cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMDELLTRA and for 2 months after the last dose

[see Use in Specific Populations (8.1, 8.3)]

)

11/2025

Administer as an intravenous infusion over 1 hour. (

2.2 Recommended Dosage and Administration

Administer IMDELLTRA as an intravenous infusion for one hour.
The recommended step-up dose and schedule for IMDELLTRA is provided in Table 1. Administer step-up dose and schedule on Cycle 1 Day 1 to reduce the incidence and severity of CRS.
After step-up dose and schedule on Cycle 1 Day 1, administer IMDELLTRA every 2 weeks until disease progression or unacceptable toxicity.

Table 1. Recommended Dose and Schedule of IMDELLTRA
Dosing Schedule	Day	Dose of IMDELLTRA	Administration Instructions	Recommended Monitoring
Note: See Table 4for recommendation on restarting IMDELLTRA after dose delays.
Step-up Dose and Schedule Cycle 1	Day 1Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3.	Step-up dose 1 mg	Administer IMDELLTRA as a 1-hour intravenous infusion in an appropriate healthcare setting.	Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the IMDELLTRA infusion accompanied by a caregiver.
	Day 8	10 mg
	Day 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusionExtended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥ 2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5and 6for monitoring recommendations.
Cycle 2	Day 1 and 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion .
Cycles 3 and 4	Day 1 and 15	10 mg		Observe patients for 3-4 hours post IMDELLTRA infusion .
Cycle 5 and subsequent infusions	Day 1 and 15	10 mg		Observe patients for 2 hours post IMDELLTRA infusion .

Administration

The intravenous (IV) catheter for concomitant medications administration can be used to administer the IMDELLTRA infusion.
To ensure patency, flush the IV catheter over 3 to 5 minutes using 0.9% Sodium Chloride for Injection.
Administer the reconstituted and diluted IMDELLTRA as a 1-hour intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. Flush the IV-line upon completion of the IMDELLTRA infusion.

Table 2 provides the infusion duration and rate.

Table 2. IMDELLTRA Infusion Duration and Rate
Infusion Duration for 250 mL IV Preparation	Infusion Rate
1 hour	250 mL/hour

)

Administer IMDELLTRA according to the step

up dosing schedule in Table 1 to reduce the risk of cytokine release syndrome. (

2.2 Recommended Dosage and Administration

Administer IMDELLTRA as an intravenous infusion for one hour.
The recommended step-up dose and schedule for IMDELLTRA is provided in Table 1. Administer step-up dose and schedule on Cycle 1 Day 1 to reduce the incidence and severity of CRS.
After step-up dose and schedule on Cycle 1 Day 1, administer IMDELLTRA every 2 weeks until disease progression or unacceptable toxicity.

Table 1. Recommended Dose and Schedule of IMDELLTRA
Dosing Schedule	Day	Dose of IMDELLTRA	Administration Instructions	Recommended Monitoring
Note: See Table 4for recommendation on restarting IMDELLTRA after dose delays.
Step-up Dose and Schedule Cycle 1	Day 1Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3.	Step-up dose 1 mg	Administer IMDELLTRA as a 1-hour intravenous infusion in an appropriate healthcare setting.	Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the IMDELLTRA infusion accompanied by a caregiver.
	Day 8	10 mg
	Day 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusionExtended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥ 2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5and 6for monitoring recommendations.
Cycle 2	Day 1 and 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion .
Cycles 3 and 4	Day 1 and 15	10 mg		Observe patients for 3-4 hours post IMDELLTRA infusion .
Cycle 5 and subsequent infusions	Day 1 and 15	10 mg		Observe patients for 2 hours post IMDELLTRA infusion .

Administration

The intravenous (IV) catheter for concomitant medications administration can be used to administer the IMDELLTRA infusion.
To ensure patency, flush the IV catheter over 3 to 5 minutes using 0.9% Sodium Chloride for Injection.
Administer the reconstituted and diluted IMDELLTRA as a 1-hour intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. Flush the IV-line upon completion of the IMDELLTRA infusion.

Table 2 provides the infusion duration and rate.

Table 2. IMDELLTRA Infusion Duration and Rate
Infusion Duration for 250 mL IV Preparation	Infusion Rate
1 hour	250 mL/hour

)

Administer concomitant medications as recommended. (

2.3 Recommended Concomitant Medications for IMDELLTRA Administration for Cycle 1 Day 1 and Cycle 1 Day 8

Administer recommended concomitant medications for IMDELLTRA during Cycle 1 Day 1 and Cycle 1 Day 8 as presented in Table 3 to reduce the risk of CRS

[see Warnings and Precautions (5.1)]

Table 3. Recommended Concomitant Medications for IMDELLTRA Administration for Cycle 1 Day 1 and Cycle 1 Day 8
Treatment Day	Medication	Administration
Cycle 1 Day 1 and Cycle 1 Day 8	Administer dexamethasone 8 mg intravenously (or equivalent)	Within 1 hour prior to IMDELLTRA administration
Cycle 1 Day 1 and Cycle 1 Day 8	Administer 1 liter of normal saline intravenously over 2 to 4 hours	Immediately after completion of IMDELLTRA infusion

)

Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting.

Recommend patients to remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from the start of the infusion with IMDELLTRA following Cycle 1 Day 1 and Cycle 1 Day 8 doses, accompanied by a caregiver. (

2.2 Recommended Dosage and Administration

Administer IMDELLTRA as an intravenous infusion for one hour.
The recommended step-up dose and schedule for IMDELLTRA is provided in Table 1. Administer step-up dose and schedule on Cycle 1 Day 1 to reduce the incidence and severity of CRS.
After step-up dose and schedule on Cycle 1 Day 1, administer IMDELLTRA every 2 weeks until disease progression or unacceptable toxicity.

Table 1. Recommended Dose and Schedule of IMDELLTRA
Dosing Schedule	Day	Dose of IMDELLTRA	Administration Instructions	Recommended Monitoring
Note: See Table 4for recommendation on restarting IMDELLTRA after dose delays.
Step-up Dose and Schedule Cycle 1	Day 1Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3.	Step-up dose 1 mg	Administer IMDELLTRA as a 1-hour intravenous infusion in an appropriate healthcare setting.	Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the IMDELLTRA infusion accompanied by a caregiver.
	Day 8	10 mg
	Day 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusionExtended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥ 2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5and 6for monitoring recommendations.
Cycle 2	Day 1 and 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion .
Cycles 3 and 4	Day 1 and 15	10 mg		Observe patients for 3-4 hours post IMDELLTRA infusion .
Cycle 5 and subsequent infusions	Day 1 and 15	10 mg		Observe patients for 2 hours post IMDELLTRA infusion .

Administration

The intravenous (IV) catheter for concomitant medications administration can be used to administer the IMDELLTRA infusion.
To ensure patency, flush the IV catheter over 3 to 5 minutes using 0.9% Sodium Chloride for Injection.
Administer the reconstituted and diluted IMDELLTRA as a 1-hour intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. Flush the IV-line upon completion of the IMDELLTRA infusion.

Table 2 provides the infusion duration and rate.

Table 2. IMDELLTRA Infusion Duration and Rate
Infusion Duration for 250 mL IV Preparation	Infusion Rate
1 hour	250 mL/hour

)

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

2.2 Recommended Dosage and Administration

Administer IMDELLTRA as an intravenous infusion for one hour.
The recommended step-up dose and schedule for IMDELLTRA is provided in Table 1. Administer step-up dose and schedule on Cycle 1 Day 1 to reduce the incidence and severity of CRS.
After step-up dose and schedule on Cycle 1 Day 1, administer IMDELLTRA every 2 weeks until disease progression or unacceptable toxicity.

Table 1. Recommended Dose and Schedule of IMDELLTRA
Dosing Schedule	Day	Dose of IMDELLTRA	Administration Instructions	Recommended Monitoring
Note: See Table 4for recommendation on restarting IMDELLTRA after dose delays.
Step-up Dose and Schedule Cycle 1	Day 1Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3.	Step-up dose 1 mg	Administer IMDELLTRA as a 1-hour intravenous infusion in an appropriate healthcare setting.	Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the IMDELLTRA infusion accompanied by a caregiver.
	Day 8	10 mg
	Day 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusionExtended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥ 2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5and 6for monitoring recommendations.
Cycle 2	Day 1 and 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion .
Cycles 3 and 4	Day 1 and 15	10 mg		Observe patients for 3-4 hours post IMDELLTRA infusion .
Cycle 5 and subsequent infusions	Day 1 and 15	10 mg		Observe patients for 2 hours post IMDELLTRA infusion .

Administration

The intravenous (IV) catheter for concomitant medications administration can be used to administer the IMDELLTRA infusion.
To ensure patency, flush the IV catheter over 3 to 5 minutes using 0.9% Sodium Chloride for Injection.
Administer the reconstituted and diluted IMDELLTRA as a 1-hour intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. Flush the IV-line upon completion of the IMDELLTRA infusion.

Table 2 provides the infusion duration and rate.

Table 2. IMDELLTRA Infusion Duration and Rate
Infusion Duration for 250 mL IV Preparation	Infusion Rate
1 hour	250 mL/hour

2.6 Preparation

Material Compatibility Information

IV bags composed of ethyl vinyl acetate (EVA), polyolefin, and polyvinyl chloride (PVC) have been shown to be compatible with IMDELLTRA at the specified administration conditions.
IV line and catheter materials composed of polyolefin, PVC, and polyurethane have been shown to be compatible with IMDELLTRA at the specified administration conditions.
The use of Closed System Transfer Device (CSTD) is not recommended due to potential wrong dose medication error risk. Amgen has not performed compatibility testing of vial adaptor CSTDs with IMDELLTRA.

Step 1: Reconstitute IMDELLTRA with Sterile Water for Injection

Table 8 provides the required amount of sterile water for injection required to reconstitute IMDELLTRA 1 mg and 10 mg vials.

Do not

use IV Solution Stabilizer (IVSS) to reconstitute IMDELLTRA

The IV Solution Stabilizer (IVSS) is used to coat the intravenous bag prior to addition of reconstituted IMDELLTRA to prevent adsorption of IMDELLTRA to IV bags and IV tubing.

Table 8. Required Amount of Sterile Water for Injection to Reconstitute IMDELLTRAEach vial contains overfill to allow for withdrawal of 1.1 mL (1 mg vial) or 4.2 mL (10 mg vial) after reconstitution to ensure delivery at the stated concentration of labeled vial strength.
IMDELLTRA Vial Strength	Amount of Sterile Water for Injection Needed to Reconstitute IMDELLTRA	Resulting Concentration
1 mg	1.3 mL	0.9 mg/mL
10 mg	4.4 mL	2.4 mg/mL

Using a needle and syringe filled with the required amount of sterile water, inject the sterile water against the glass vial. Avoid injecting the water directly onto the powder to prevent foaming.
Gently swirl the contents to mix. Do not shake.
Inspect parenteral drug products for particulate matter and discoloration prior to administration. Inspect that the solution is clear to opalescent, colorless to slightly yellow. Do not use if the solution is cloudy or has particulates.
Further dilute reconstituted IMDELLTRA.
The reconstituted IMDELLTRA must be further diluted within 4 hours of reconstitution or discarded.

Prepare the infusion bag: Steps 2 to 5

Step 2 : Withdraw 0.9% Sodium Chloride for Injection

Using a 250 mL prefilled bag of 0.9% Sodium Chloride for Injection, withdraw the amount of sodium chloride specified in Table 9 and discard.

Table 9. Required Amount of 0.9% Sodium Chloride to Withdraw from 250 mL IV Bag
IMDELLTRA Vial Strength	IMDELLTRA Dose	Volume of 0.9% Sodium Chloride to Withdraw From 250 mL IV Bag
1 mg	1 mg	14 mL
10 mg	10 mg	17 mL

Step 3: Add IV Solution Stabilizer to the infusion bag

Inject 13 mL of IV Solution Stabilizer (IVSS) into the 250 mL 0.9% Sodium Chloride infusion bag
,
see Table 10
.
Gently mix the contents of the infusion bag to avoid foaming. Do not shake.

Table 10. Required Amount of IV Solution Stabilizer (IVSS) to Add to IV Bag
IMDELLTRA Vial Strength	IMDELLTRA Dose	Volume of IV Solution Stabilizer (IVSS) to Add to IV Bag
1 mg	1 mg	13 mL
10 mg	10 mg	13 mL

Step 4: Dilute the reconstituted IMDELLTRA into the infusion bag

Transfer the required volume of reconstituted IMDELLTRA listed in Table 11 to the infusion bag
(containing IV Solution Stabilizer)
.

NOTE: The final concentrations for the different strength vials are NOT the same following reconstitution and further dilution.

Table 11. Required Amount of Reconstituted IMDELLTRA to Add to 250 mL IV Bag
IMDELLTRA Vial Strength	IMDELLTRA Dose	Volume of Reconstituted IMDELLTRA to Add to 250 mL IV Bag
1 mg	1 mg	1.1 mL
10 mg	10 mg	4.2 mL

Gently mix the contents of the bag. Do not shake.

Step 5: Remove air from IV bag

Remove air from the prepared IV bag using an empty syringe to avoid foaming.

Step 6: Prime IV tubing

Prime intravenous tubing with either 0.9% Sodium Chloride for Injection or with the final prepared product.
See Table 12for maximum storage time of prepared IMDELLTRA infusion.

Prepared IMDELLTRA Infusion Bag Storage Requirements

Administer reconstituted and diluted IMDELLTRA immediately.
Table 12 displays the maximum storage time for the prepared IMDELLTRA infusion bag.
Maximum storage time includes total duration from the time of reconstitution of the vial of IMDELLTRA to the end of the infusion.

Table 12. Maximum Storage Time for Prepared IMDELLTRA Infusion Bag
	Room Temperature 20°C to 25°C (68°F to 77°F)	Refrigerated 2°C to 8°C (36°F to 46°F)
Prepared IMDELLTRA Infusion Bag	8 hours	7 days
Discard the prepared IMDELLTRA infusion bag after maximum storage time (from time of reconstitution). If refrigerated, allow the prepared IMDELLTRA infusion bag to come room temperature prior to administration, and complete the infusion within 8 hours (including preparation and infusion time). Do not re-refrigerate prepared infusion bag.

)

Lactation

: Advise not to breastfeed. (

8.2 Lactation

Risk Summary

There are no data on the presence of tarlatamab-dlle in human milk or the effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to IMDELLTRA are unknown. Because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with IMDELLTRA and for 2 months after the last dose.

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