DANYELZA Solution for injection Ref.[108705] Active ingredients: Naxitamab

Source: FDA, National Drug Code (US) Revision Year: 2023

1. Indications and Usage

DANYELZA is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy.

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 Recommended Dosage

The recommended dosage of DANYELZA is 3 mg/kg/day (up to 150 mg/day) on Days 1, 3, and 5 of each treatment cycle, administered as an intravenous infusion after dilution [see Dosage and Administration (2.4 and 2.5)] in combination with GM-CSF subcutaneously as shown in Table 1. Refer to the GM-CSF Prescribing Information for recommended dosing information.

Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by 5 additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks. Discontinue DANYELZA and GM-CSF for disease progression or unacceptable toxicity.

Administer pre-infusion medications and supportive treatment, as appropriate, during infusion [see Dosage and Administration (2.2)].

The recommended dosage regimen for each treatment cycle is described below and in Table 1:

Days -4 to 0: administer GM-CSF 250 µg/m²/day by subcutaneous injection, beginning 5 days prior to DANYELZA infusion.
Days 1 to 5: administer GM-CSF 500 µg/m²/day by subcutaneous injection. Administer at least 1 hour prior to DANYELZA administration on Days 1, 3, and 5.
Days, 1, 3, and 5: administer DANYELZA 3 mg/kg/day (up to 150 mg/day) by intravenous infusion.

Table 1. Dose and Schedule of GM-CSF and DANYELZA Within One Treatment Cycle:

Day	-4	-3	-2	-1	0	1	2	3	4	5
Subcutaneous GM-CSF	250 µg/m²/day					500 µg/m²/day
Intravenous DANYELZA						3 mg/kg/day		3 mg/kg/day		3 mg/kg/day

Missed Dose

If a DANYELZA dose is missed, administer the missed dose the following week by Day 10. Administer GM-CSF 500 µg /m²/day on the first day of the DANYELZA infusion, and on the day before and on the day of the second and third infusion, respectively (i.e. a total of 5 days with 500 µg /m²/day).

Pain Management Prior to and During Infusion [see Warnings and Precautions (5.2)]:

Five days prior to the first infusion of DANYELZA in each cycle, initiate a 12-day course (Day -4 through Day 7) of prophylactic medication for neuropathic pain, such as gabapentin.
Administer oral opioids 45-60 minutes prior to initiation of each DANYELZA infusion and additional intravenous opioids as needed for breakthrough pain during the infusion.
Consider use of ketamine for pain that is not adequately controlled by opioids.

Premedication: Reduce Risk of Infusion-Related Reactions and Nausea/Vomiting [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]:

Administer intravenous corticosteroids (e.g. methylprednisolone 2 mg/kg with maximum dose of 80 mg or equivalent corticosteroid dose) 30 minutes to 2 hours prior to the first infusion of DANYELZA. Administer corticosteroid premedication for subsequent infusions if a severe infusion reaction occurred with the previous infusion or during the previous cycle.
Administer an antihistamine, an H2 antagonist, acetaminophen and an antiemetic 30 minutes prior to each infusion.

2.3 Dosage Modifications for Adverse Reactions

The recommended dosage modifications for DANYELZA for adverse reactions are presented in Table 2.

Table 2. Recommended DANYELZA Dosage Modifications for Adverse Reactions:

Adverse Reaction	Severity*	Dosage Modifications
Infusion-related reactions [see Warnings and Precautions (5.1)]	Grade 2 Defined as: Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated for ≤24 hours	• Reduce DANYELZA infusion rate to 50% of previous rate and monitor closely until recovery to Grade ≤ 1 • Increase infusion rate gradually to rate prior to the event as tolerated
	Grade 3 Defined as: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae	• Immediately interrupt DANYELZA infusion and monitor closely until recovery to Grade ≤ 2 • Resume infusion at 50% of the rate prior to the event and increase infusion rate gradually to infusion rate prior to the event as tolerated. • Permanently discontinue DANYELZA in patients not responding to medical intervention.
	Grade 4 infusion-related reactions Defined as: Life-threatening consequences: urgent intervention indicated or Grade 3 or 4 anaphylaxis	• Permanently discontinue DANYELZA
Pain [see Warnings and Precautions (5.2)]	Grade 3 unresponsive to maximum supportive measures	• Permanently discontinue DANYELZA
Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.2)]	All Grades	• Permanently discontinue DANYELZA
Transverse myelitis [see Warnings and Precautions (5.2)]	All Grades	• Permanently discontinue DANYELZA
Peripheral neuropathy [see Warnings and Precautions (5.2)]	Motor neuropathy: Grade 2 or greater or Sensory neuropathy: Grade 3 or 4	• Permanently discontinue DANYELZA
Neurological disorders of the eye [see Warnings and Precautions (5.2)]	Grade 2 to 4 resulting in decreased visual acuity or limiting activities of daily living	• Withhold DANYELZA until resolution • If resolved resume DANYELZA at 50% of the prior dose; if tolerated without recurrence of symptoms, gradually increase DANYELZA to dose prior to onset of symptoms • Permanently discontinue DANYELZA if not resolved within 2 weeks or upon recurrence
	Subtotal or total vision loss	• Permanently discontinue DANYELZA
Prolonged urinary retention [see Warnings and Precautions (5.2)]	Persisting following discontinuation of opioids	• Permanently discontinue DANYELZA
Hypertension [see Warnings and Precautions (5.3)]	Grade 3	• Withhold DANYELZA or pause infusion until recovery to ≤ Grade 2 • Resume infusion at 50% of prior rate; if tolerated without recurrence of symptoms, gradually increase DANYELZA to rate prior to onset of symptoms • Permanently discontinue DANYELZA in patients not responding to medical intervention
Hypertension [see Warnings and Precautions (5.3)]	Grade 4	• Permanently discontinue DANYELZA
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 3	• Withhold DANYELZA until recovery to Grade ≤ 2 • If resolved to Grade ≤ 2 resume DANYELZA at same rate • Permanently discontinue DANYELZA if not resolved to Grade ≤2 within 2 weeks
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 4	• Permanently discontinue DANYELZA

^* Based on Common Terminology Criteria for Adverse Events (CTCAE) v 5.0

2.4 Preparation

Use appropriate aseptic technique.
Visually inspect vial for particulate matter and discoloration prior to administration. Discard vial if solution is discolored, cloudy, or contains particulate matter.
Add appropriate quantities of 5% Albumin (Human), USP and 0.9% Sodium Chloride Injection, USP to an empty, sterile intravenous infusion bag large enough to hold the volume needed for the relevant dose as indicated in Table 3. Allow for 5-10 minutes of passive mixing.
Withdraw the required dose of DANYELZA and inject into the infusion bag containing the 5% Albumin (Human), USP and 0.9% Sodium Chloride Injection, USP. Discard any unused portion of DANYELZA left in the vial.

Preparation instructions for DANYELZA are described in Table 3.

Table 3. Preparation of DANYELZA, 4 mg/ml:

DANYELZA dose (mg)	DANYELZA volume (mL)	Volume of 5% Albumin (Human), USP (mL)	Total infusion volume achieved by adding sufficient 0.9% Sodium Chloride Injection, USP (mL)	Final concentration of prepared DANYELZA infusion (mg/mL)
≤80	≤20	10	50	≤1.6
81 to 120	>20 to 30	15	75	1.1 to 1.6
121 to 160	>30 to 40	20	100	1.2 to 1.6
161 to 200	>40 to 50	25	125	1.3 to 1.6
201 to 240	>50 to 60	30	150	1.3 to 1.6
241 to 280	>60 to 70	35	175	1.4 to 1.6

If not used immediately, store the diluted DANYELZA infusion solution at room temperature (15°C to 25°C [59ºF to 77ºF]) for up to 8 hours or refrigerate (2°C to 8°C [36°F to 46°F]) for up to 24 hours. Once removed from refrigeration, initiate infusion within 8 hours.

2.5 Administration

Administer DANYELZA as a diluted intravenous infusion as recommended. Do not administer DANYELZA as an intravenous push or bolus [see Dosage and Administration (2.4)].
For the first infusion (Cycle 1, Day 1), administer DANYELZA intravenously over 60 minutes.

For subsequent infusions, administer DANYELZA intravenously over 30 to 60 minutes, as tolerated [see Dosage and Administration (2.1, 2.3)].

Observe patients for a minimum of 2 hours following each infusion.

16.2. Storage and Handling

Store DANYELZA vial refrigerated at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light until time of use.

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