IMDELLTRA Solution for injection Ref.[110074] Active ingredients: Tarlatamab

Source: FDA, National Drug Code (US) Revision Year: 2024

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.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2. Dosage and Administration

2.1 Important Dosing Information

Administer IMDELLTRA according to the step-up dosing schedule in Table 1 to reduce the incidence and severity of cytokine release syndrome (CRS) [see Dosage and Administration (2.2)].
For Cycle 1, administer recommended concomitant medications in Table 3 before and after Cycle 1 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 that patients 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.
Prior to administration of IMDELLTRA evaluate complete blood count, liver enzymes and bilirubin before each dose, and as 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)].

2.2 Recommended Dosage and Administration

Administer IMDELLTRA as an intravenous infusion over one hour.
The recommended step-up dosage schedule for IMDELLTRA is provided in Table 1. Administer following step-up dosing to reduce the incidence and severity of CRS.
After step-up dosing schedule, administer IMDELLTRA biweekly (every 2 weeks) until disease progression or unacceptable toxicity.

Table 1. Recommended Dosage and Schedule of IMDELLTRA:

Dosing Schedule	Day	Dose of IMDELLTRA	Administration Instructions	Recommended Monitoring
Step-up Dosing Schedule Cycle 1	Day 1^a	Step-up dose^a 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 infusion with IMDELLTRA, accompanied by a caregiver.
	Day 8^a	10 mg^a
	Day 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion^b.
Cycle 2	Day 1 and 15	10 mg		Observe patients for 6-8 hours post IMDELLTRA infusion^b.
Cycles 3 and 4	Day 1 and 15	10 mg		Observe patients for 3-4 hours post IMDELLTRA infusion^b.
Cycle 5 and subsequent infusions	Day 1 and 15	10 mg		Observe patients for 2 hours post IMDELLTRA infusion^b.

^a Administer recommended concomitant medications before and after Cycle 1 IMDELLTRA infusions as described in Table 3.
^b Extended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5 and 6 for monitoring recommendations.
Note: see Table 4 for recommendation on restarting IMDELLTRA after dose delays.

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 3-5 mins using 0.9% Sodium Chloride for Injection.
Administer the reconstituted and diluted IMDELLTRA as an intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm.
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

Administer recommended concomitant medications for IMDELLTRA administration during Cycle 1 as presented in Table 3 to reduce the risk of cytokine release syndrome [see Warnings and Precautions (5.1)].

Table 3. Recommended Concomitant Medications for IMDELLTRA Administration for Cycle 1:

Treatment Day	Medication	Administration
Day 1 and Day 8	Administer 8 mg of dexamethasone intravenously (or equivalent)	Within 1-hour prior to IMDELLTRA administration
Day 1, Day 8 and Day 15	Administer 1 liter of normal saline intravenously over 4-5 hours	Immediately after completion of IMDELLTRA infusion

2.4 Restarting IMDELLTRA After Dosage Delay

If a dose of IMDELLTRA is delayed, restart therapy based on the recommendation as listed in Table 4 and resume the dosing schedule accordingly [see Dosage and Administration (2.2)]. Administer recommended concomitant medications as indicated in section 2.3.

Table 4. Recommendations for Restarting Therapy with IMDELLTRA After Dosage Delay:

Last Dose Administered	Time Since the Last Dose Administered	Action^a
1 mg on Cycle 1 Day 1	2 weeks or less (≤14 days)	Administer IMDELLTRA 10 mg, then resume with the planned dosage 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 dosage schedule.
10 mg on Cycle 1 Day 8	3 weeks or less (≤21 days)	Administer IMDELLTRA 10 mg, then resume with the planned dosage 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 dosage 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 dosage 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 dosage schedule.

^a Administer recommended concomitant medications before and after Cycle 1 IMDELLTRA infusions and monitor patients accordingly [see Dosage and Administration (2.1, 2.2 and 2.3)].

2.5 IMDELLTRA Dosage Modifications and Adverse Reaction Management

No dose reduction for IMDELLTRA is recommended. See Table 5 and Table 6 for recommended actions for the 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 Syndrome^a:

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 dose^b.	• Administer symptomatic treatment (e.g., acetaminophen) for fever.
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^b.	• 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^c (or equivalent) 8 mg IV. • Consider tocilizumab (or equivalent). When resuming treatment at 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 ≥38°C with: • Hemodynamic instability requiring a vasopressor (with or without vasopressin) or • Worsening hypoxia or respiratory distress requiring high flow nasal canula (>6 L/min oxygen) or face mask.	Withhold IMDELLTRA until the event resolves, then resume IMDELLTRA at the next scheduled dose^b. 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 (see Table 3). When resuming treatment at 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). • Worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure.	Permanently discontinue IMDELLTRA.	• ICU care. • Per Grade 3 treatment. • Recommend tocilizumab (or equivalent).

^a CRS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (2019).
^b See Table 4 for recommendations on restarting IMDELLTRA after dose delays [see Dosage and Administration (2.4)].
^c Taper steroids per standard of care guidelines.

Table 6. Guidelines for Management of Neurologic Toxicity including Immune Effector Cell-Associated Neurotoxicity Syndrome^a:

ICANS Grade^a	Defining Symptoms	IMDELLTRA Dosage Modifications	Management
Grade 1^a	ICE score 7-9^b with no depressed level of consciousness.	• Withhold IMDELLTRA until ICANS resolves, then resume IMDELLTRA at the next scheduled dose^c.	• Supportive care.
Grade 2^a	ICE score 3-6^b and/or mild somnolence awaking to voice.	• Withhold IMDELLTRA until ICANS resolves, then resume IMDELLTRA at the next scheduled dose^c.	• Supportive care. • Dexamethasone^d (or equivalent) 10 mg IV. Can repeat every 6 hours or methylprednisolone 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 for 22 to 24 hours following the next dose of IMDELLTRA.
Grade 3^a	ICE score 0-2^b 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^c. • If there is no improvement to grade ≤1 within 7 days or grade 3 toxicity reoccurs within 7 days of reinitiation, permanently discontinue IMDELLTRA. • For recurrent grade 3 events, permanently discontinue.	• Recommend intensive monitoring, e.g., ICU care. • Consider mechanical ventilation for airway protection. Dexamethasone^d (or equivalent) 10 mg IV every 6 hours or methylprednisolone 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 for 22 to 24 hours following the next dose of IMDELLTRA.
Grade 4^a	ICE score 0^b (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^d. • Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent Grade ≥ 3 neurotoxicity. • Treat convulsive status epilepticus per institutional guidelines.

^a ICANS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (2019).
^b If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (names 3 objects, e.g., point to clock, pen, button = 3 points); Following commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.
^c See Table 4 for recommendations on restarting IMDELLTRA after dose delays [see Dosage and Administration (2.4)].
^d Taper steroids per standard of care guidelines.

Table 7. Recommended Treatment Interruptions of IMDELLTRA for the Management of Cytopenias, Infections, and Other Adverse Reactions:

Adverse Reactions	Severity^b	Dosage Modification^a
Cytopenias [see Warnings and Precautions (5.3)]	Grade 3 or 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 3 weeks.
	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^a.
	Grade 4	Permanently discontinue IMDELLTRA.
Hepatotoxicity [see Warnings and Precautions (5.5)]	Grade 3 Increased ALT or AST or bilirubin	Withhold IMDELLTRA until adverse events improve 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.

^a Refer to Table 4 for dose restarting guidance.
^b Severity based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.

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 IMDELLTRA^a:

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

^a Each 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.

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 12 for 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:

	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 IMDELLTRA infusion after maximum storage time (from time of reconstitution).
Do not re-refrigerate prepared infusion bag.

16.2. Storage and Handling

Store IMDELLTRA and IV Solution Stabilizer (IVSS) vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. Do not freeze. IMDELLTRA and IV Solution Stabilizer (IVSS) vials may be kept at room temperature between 20°C to 25°C (68°F to 77°F) for up to 24 hours in the original carton to protect from light.

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