Danyelza Injection
FDA Label NDC 50633-230

Serious Infusion-Related Reactions

DANYELZA can cause serious infusion reactions, including cardiac arrest, anaphylaxis, hypotension, bronchospasm, and stridor. Infusion reactions of any Grade occurred in 94-100% of patients. Severe infusion reactions occurred in 32-68% and serious infusion reactions occurred in 4 - 18% of patients in DANYELZA clinical studies [see Warnings and Precautions (5.1)]. Premedicate prior to each DANYELZA infusion as recommended and monitor patients for at least 2 hours following completion of each infusion. Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity [see Dosage and Administration (2.2, 2.3), Contraindications (4), and Warnings and Precautions (5.1)].

Neurotoxicity

DANYELZA can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis and reversible posterior leukoencephalopathy syndrome (RPLS). Pain of any Grade occurred in 94-100% of patients in DANYELZA clinical studies [see Warnings and Precautions (5.2)]. Premedicate to treat neuropathic pain as recommended. Permanently discontinue DANYELZA based on the adverse reaction and severity [see Dosage and Administration (2.2, 2.3)and Warnings and Precautions (5.2)].

Missed Dose

If a DANYELZA dose is missed, administer the missed dose the following week by Day 10. Administer GM-CSF 500 µg /m ²/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 /m ²/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.

Pain

Pain, including abdominal pain, bone pain, neck pain, and extremity pain, occurred in 100% of patients in Study 201 and 94% of patients in Study 12-230. Grade 3 pain occurred in 72% of patients in Study 201. One patient in Study 201 (4%) required interruption of an infusion due to pain. Pain typically began during the infusion of DANYELZA and lasted a median of less than one day in Study 201 (range less than one day and up to 62 days) [see Adverse Reactions (6.1)] .

Premedicate with drugs that treat neuropathic pain (e.g., gabapentin) and oral opioids. Administer intravenous opioids as needed for breakthrough pain [see Dosage and Administration (2.2)]. Permanently discontinue DANYELZA based on severity [see Dosage and Administration (2.3)].

Transverse Myelitis

Transverse myelitis has occurred with DANYELZA. Permanently discontinue DANYELZA in patients who develop transverse myelitis [see Dosage and Administration (2.3)] .

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Reversible posterior leukoencephalopathy syndrome (RPLS) (also known as posterior reversible encephalopathy syndrome or PRES) occurred in 2 (2.8%) patients in Study 12-230. Events occurred 2 and 7 days following completion of the first cycle of DANYELZA. Monitor blood pressure during and following DANYELZA infusion and assess for neurologic symptoms [see Warnings and Precautions (5.3)] . Permanently discontinue DANYELZA in case of symptomatic RPLS [see Dosage and Administration (2.3)and Adverse Reactions (6.1)] .

Peripheral Neuropathy

Peripheral neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, and neuralgia, occurred in 32% of patients in Study 201 and in 25% of patients in Study 12-230. Most signs and symptoms of neuropathy began on the day of the infusion and neuropathy lasted a median of 5.5 days (range 0 to 22 days) in Study 201 and 0 days (range 0 to 22 days) in Study 12-230 [see Adverse Reactions (6.1)] .

Permanently discontinue DANYELZA based on severity [see Dosage and Administration (2.3)] .

Neurological Disorders of the Eye

Neurological disorders of the eye including unequal pupils, blurred vision, accommodation disorder, mydriasis, visual impairment, and photophobia occurred in 24% of patients in Study 201 and 19% of patients in Study 12-230. Neurological disorders of the eye lasted a median of 17 days (range 0 to 84 days) in Study 201 with two patients (8%) experiencing an event that had not resolved at the time of data cutoff, and a median of 1 day (range less than one day to 21 days) in Study 12-230. Permanently discontinue DANYELZA based on severity [see Dosage and Administration (2.3)and Adverse Reactions (6.1)].

Prolonged Urinary Retention

Urinary retention occurred in 1 (4%) patient in Study 201 and in 3 patients (4%) in Study 12-230. All events in both studies occurred on the day of an infusion of DANYELZA and lasted between 0 and 24 days. Permanently discontinue DANYELZA in patients with urinary retention that does not resolve following discontinuation of opioids [see Dosage and Administration (2.3)and Adverse Reactions (6.1)].

Study 201

In Study 201, among 25 patients who received DANYELZA in combination with GM-CSF, 12% were exposed for 6 months or longer and none were exposed for greater than one year.

Serious adverse reactions occurred in 32% of patients who received DANYELZA in combination with GM-CSF. Serious adverse reactions in more than one patient included anaphylactic reaction (12%) and pain (8%). Permanent discontinuation of DANYELZA due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of DANYELZA included anaphylactic reaction (8%) and respiratory depression (4%).

Dosage interruptions of DANYELZA due to an adverse reaction occurred in 84% of patients. Adverse reactions requiring dosage interruption in > 10% of patients included hypotension and bronchospasm.

Table 4 summarizes adverse reactions in Study 201.

Table 4. Adverse Reactions (>10%) in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received DANYELZA with GM-CSF in Study 201

	DANYELZA with GM-CSF Adverse reactions were graded using CTCAE version 4.0. (n=25)
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
Body system
General disorders and administration site conditions
Pain Pain includes pain, abdominal pain, pain in extremity, bone pain, neck pain, back pain, and musculoskeletal pain.	100	72
Infusion-related reaction Infusion-related reaction includes hypotension, bronchospasm, flushing, wheezing, stridor, urticaria, dyspnea, pyrexia, infusion-related reaction, face edema, edema mouth, tongue edema, lip edema, respiratory tract edema, chills, hypoxia, pruritis and rash occurring on the day of infusion or the day following an infusion.	100	68
Edema	28	0
Fatigue Fatigue includes fatigue, asthenia.	28	0
Pyrexia Pyrexia not occurring on the day of infusion or the day following an infusion	28	0
Respiratory, thoracic and mediastinal disorders
Cough	60	0
Rhinorrhea	24	0
Vascular disorders
Hypertension	44	4
Gastrointestinal disorders
Vomiting	60	4
Diarrhea	56	8
Nausea	56	0
Skin and subcutaneous tissue disorders
Urticaria Urticaria, not occurring on the day of infusion or the day following an infusion	32	4
Cardiac disorders
Tachycardia Tachycardia includes sinus tachycardia and tachycardia	84	4
Nervous system disorders
Peripheral neuropathy Peripheral neuropathy includes peripheral sensory neuropathy, paresthesia, neuralgia.	32	0
Headache	28	8
Depressed level of consciousness	24	16
Eye disorders
Neurological disorders of the eye Neurological disorders of the eye includes unequal pupils, blurred vision, and mydriasis.	24	0
Immune system disorders
Anaphylactic reaction	12	12
Metabolism and nutrition disorders
Decreased appetite	16	0
Infections and infestations
Influenza	12	0
Rhinovirus infection	12	0
Upper respiratory tract infection	12	0
Investigations
Weight decreased	12	0
Psychiatric disorders
Anxiety	12	0

Clinically relevant adverse reactions occurring in ≤10% of patients who received DANYELZA with GM-CSF included peripheral edema (8%).

Table 5 summarizes the laboratory abnormalities in Study 201.

Table 5. Selected Laboratory Abnormalities (>20%) Worsening from Baseline in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received DANYELZA with GM-CSF in Study 201

Laboratory Abnormality	DANYELZA with GM-CSF The table presents laboratory parameters with available grading according to CTCAE version 4.0. Baseline evaluation was the last non-missing value prior to first DANYELZA dosing. Each test incidence is based on the number of patients who had both a baseline value and at least one on-study laboratory measurement (range: 23 to 24 patients). n=25
	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Decreased potassium	63	8
Decreased albumin	50	0
Increased alanine aminotransferase	42	8
Decreased sodium	29	0
Hematology
Decreased lymphocytes	74	30
Decreased platelet count	65	17
Decreased neutrophils	61	39
Decreased hemoglobin	48	4

Study 12-230

In Study 12-230, among 72 patients who received DANYELZA in combination with GM-CSF, 32% were exposed for 6 months or longer and 8% were exposed for greater than one year.

Serious adverse reactions occurred in 40% of patients who received DANYELZA in combination with GM-CSF. Serious adverse reactions in > 5% of patients included hypertension (14%), hypotension (11%), and pyrexia (8%). Permanent discontinuation of DANYELZA due to an adverse reaction occurred in 8% of patients. Four (6%) patients permanently discontinued DANYELZA due to hypertension and one (1.4%) patient discontinued due to RPLS.

Table 6 summarizes adverse reactions in Study 12-230.

Table 6. Adverse Reactions (>10%) in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received DANYELZA with GM-CSF in Study 12-230

	DANYELZA with GM-CSF In Study 12-230, all adverse reactions occurring in Cycle 1 and 2, and adverse reactions of ≥ Grade 3 severity occurring in subsequent cycles were reported. In the dose finding phase, Grade 2 unexpected adverse reactions were also reported for Cycles 3 and later. , Adverse reactions were graded using CTCAE version 4.0. (n=72)
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
Body system
General disorders and administration site conditions
Infusion-related reaction Infusion-related reaction includes hypotension, bronchospasm, flushing, wheezing, stridor, urticaria, dyspnea, pyrexia, face edema, periorbital edema, lip swelling, swollen tongue, chills, hypoxia, pruritis, rash maculopapular and rash erythematous occurring on the day of infusion or the day following an infusion.	94	32
Pain Pain includes pain, abdominal pain, pain in extremity, bone pain, neck pain, back pain, non-cardiac chest pain, flank pain, and musculoskeletal pain.	94	2.8
Fatigue Fatigue includes fatigue, asthenia.	44	0
Injection site reaction	28	0
Localized edema	25	0
Pyrexia Pyrexia not occurring on the day of infusion or the day following an infusion.	11	0
Vascular disorders
Hypertension	28	7
Gastrointestinal disorders
Vomiting	63	2.8
Nausea	57	1.4
Diarrhea	50	4.2
Constipation	15	0
Skin and subcutaneous tissue disorders
Erythema multiforme	33	0
Hyperhidrosis	17	0
Erythema	11	0
Respiratory, thoracic and mediastinal disorders
Cough	57	0
Oropharyngeal pain	15	0
Rhinorrhea	15	0
Nervous system disorders
Peripheral neuropathy Peripheral neuropathy includes peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, neuralgia.	25	0
Headache	18	0
Lethargy	14	0
Metabolism and nutrition disorders
Decreased appetite	53	4.2
Cardiac disorders
Sinus tachycardia	44	1.4
Psychiatric disorders
Anxiety	26	0
Irritability	25	0
Investigations
Breath sounds abnormal	15	0
Injury and procedural complications
Contusion	15	0
Infections and infestations
Rhinovirus infection	14	0
Enterovirus infection	13	0
Eye Disorders
Neurological disorders of the eye Neurological disorders of the eye includes unequal pupils, blurred vision, accommodation disorder, visual impairment and photophobia.	19	0

Clinically relevant adverse reactions in ≤10% of patients who received DANYELZA with GM-CSF included apnea (4.2%), hypopnea (2.8%), generalized edema (2.8%), peripheral edema (8.3%), and device related infection (4.2%).

Table 7 summarizes the laboratory abnormalities in Study 12-230.

Table 7. Selected Laboratory Abnormalities (>20%) Worsening from Baseline in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received DANYELZA with GM-CSF in Study 12-230

Laboratory Abnormality	DANYELZA with GM-CSF The table presents laboratory parameters with available grading according to CTCAE version 4.0. Baseline evaluation was the last non-missing value prior to first DANYELZA dosing. Each test incidence is based on the number of patients who had both a baseline value and at least one on-study laboratory measurement (range 19 to 72 patients). n=72
	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Increased glucose	74	0
Decreased albumin	68	7
Decreased calcium	64	8
Increased alanine aminotransferase	55	9
Decreased magnesium	54	0
Increased aspartate aminotransferase	49	4
Decreased phosphate	47	5
Decreased potassium	47	32
Decreased sodium	38	6
Decreased glucose	29	8
Hematology
Decreased lymphocytes	79	56
Decreased hemoglobin	76	42
Decreased neutrophils	72	46
Decreased platelets	71	40

Risk Summary

Based on its mechanism of action, DANYELZA may cause fetal harm when administered to pregnant women [see Clinical Pharmacology (12.1)]. There are no available data on the use of DANYELZA in pregnant women and no animal reproduction studies have been conducted with DANYELZA. IgG1 monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Advise pregnant women of potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Risk Summary

There are no data on the presence of naxitamab-gqgk in human milk or its effects on the breastfed child, or on milk production, however, human IgG is present in human milk. Because of the potential for serious adverse reactions in a breastfed child from DANYELZA, advise women not to breastfeed during treatment and for 2 months after the last dose of DANYELZA.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating DANYELZA.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of DANYELZA.

Elimination

The mean terminal half-life of naxitamab-gqgk was 8.2 days.

Metabolism

Naxitamab-gqgk is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations

Population pharmacokinetic analyses suggest that age (range: 1 to 34 years), sex and race have no clinically important effect on the clearance (CL) of naxitamab-gqgk. The naxitamab-gqgk systemic exposure (AUC) at 150 mg/day (450 mg per cycle) for patients with body weight over 50 kg is not expected to differ clinically from that of the naxitamab-gqgk exposures at 3 mg/kg/day (9 mg/kg per cycle) for patients with body weight of 30 - 50 kg.

Study 201

The efficacy of DANYELZA in combination with GM-CSF was evaluated in Study 201 (NCT03363373), a multicenter open-label, single arm trial, in a subpopulation of patients who had refractory or relapsed high-risk neuroblastoma in the bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg on Days 1, 3 and 5 of each cycle. Patients received GM-CSF subcutaneously at 250 µg/m ²/day on Days -4 to 0 and at 500 µg/m ²/day on Days 1 to 5. Preplanned radiation to the primary site was allowed.

The major efficacy outcome measure was overall response rate (ORR) according to the revised International Neuroblastoma Response Criteria (INRC), as determined by independent pathology and imaging review and confirmed by at least one subsequent assessment. An additional efficacy outcome measure was duration of response (DOR).

Of the 22 patients included in the efficacy analysis, 64% had refractory disease and 36% had relapsed disease; the median age was 5 years (range 3 to 10 years), 59% were male; 45% were White, 50% were Asian and 5% were Black. MYCN amplification was present in 14% of patients and 86% of patients were International Neuroblastoma Staging System (INSS) stage 4 at time of diagnosis. Disease sites included 59% in the bone only, 9% in bone marrow only, and 32% in both. Prior therapies included surgery (91%), chemotherapy (95%), radiation (36%), autologous stem cell transplant (ASCT) (18%), and anti-GD2 antibody treatment (18%).

Efficacy results for Study 201 are described in Table 8.

Table 8. Efficacy Results from Study 201

	DANYELZA with GM-CSF (n=22)
CI = confidence interval NE: not estimable.
Overall response rate Overall response rate is defined as a complete or partial response according to the revised INRC (2017) that was confirmed by at least one subsequent assessment. Responses were observed in the bone, bone marrow, or both bone and bone marrow. (95% CI)	45% (24%, 68%)
Complete response rate	36%
Partial response rate	9%
Duration of response
Median (95% CI), months	6.2 (4.9, NE)
Responders with DOR ≥ 6 months	30%

In an exploratory analysis in the subset of patients previously treated with an anti-GD2 antibody (n=4), one patient demonstrated a confirmed complete response and no patients demonstrated a partial response.

Study 12-230

The efficacy of DANYELZA in combination with GM-CSF was evaluated in Study 12-230 (NCT01757626), a single center, open-label, single arm trial, in a subpopulation of patients who had relapsed or refractory high-risk neuroblastoma in bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients were required to have received at least one dose of DANYELZA at a dose of 3 mg/kg or greater per infusion and have evaluable disease at baseline according to independent review per the revised INRC.

Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (on Days 1, 3 and 5) in the first week of each cycle. Patients received GM-CSF subcutaneously at 250 µg/m ²/day on Days -4 to 0 and at 500 µg/m ²/day on Days 1 to 5. Radiation to non-target bony lesions and soft tissue lesions was permitted at the investigator's discretion; assessment of response excluded sites that received radiation. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by independent pathology and imaging review according to the revised INRC and confirmed by at least one subsequent assessment.

Of the 38 patients included in the efficacy analysis, 55% had relapsed neuroblastoma and 45% had refractory disease; 50% were male, the median age was 5 years (range 2 to 23 years), 74% were White, 8% Asian and 5% were Black, 5% Native American/American Indian/Alaska Native, 3% other races and 5% was not available. MYCN-amplification was present in 16% of patients and most patients were International Neuroblastoma Staging System (INSS) stage 4 (95%). Fifty percent (50%) of patients had disease involvement in the bone only, 11% only in bone marrow, and 39% in both. Prior therapies included surgery (100%), chemotherapy (100%), radiation (47%), autologous stem cell transplant (ASCT) (42%), and anti-GD2 antibody treatment (58%).

Efficacy results are provided in Table 9.

Table 9. Efficacy Results from Study 12-230

	DANYELZA with GM-CSF (n=38)
CI = confidence interval
Overall response rate Overall response rate is defined as a complete or partial response according to the revised INRC (2017) that was confirmed by at least one subsequent assessment. Responses were observed in the bone, bone marrow, or both bone and bone marrow. (95% CI)	34% (20%, 51%)
Complete response rate	26%
Partial response rate	8%
Duration of Response
Responders with DOR ≥ 6 months	23%

In an exploratory analysis in the subset of patients previously treated with an anti-GD2 antibody (n=22), the ORR was 18% (95% CI 5%, 40%), with no patients having a documented response of 6 months or greater.

Serious Infusion-Related Reactions

Advise patients and caregivers that DANYELZA can cause serious infusion-related reactions and anaphylaxis and to immediately report any signs or symptoms, such as facial or lip swelling, urticaria, or difficulty breathing, that occur during or following the infusion [see Warnings and Precautions (5.1)] .

Neurotoxicity

Advise patients and caregivers that DANYELZA can cause neurotoxicity, including severe pain, peripheral neuropathy, neurological disorders of the eye, prolonged urinary retention, transverse myelitis, and reverse posterior leukoencephalopathy syndrome. Advise patients to contact their healthcare provider for any new or worsening neurological symptoms [see Warnings and Precautions (5.2)].

Myocarditis

Advise patients and caregivers that myocarditis has been seen in patients taking DANYELZA and to report any signs or symptoms, such as chest pain, shortness of breath or abnormal heart rhythms during treatment with DANYELZA [see Warnings and Precautions (5.3)].

Hypertension

Advise patients and caregivers that DANYELZA can cause hypertension and to immediately report signs or symptoms of hypertension [see Warnings and Precautions (5.4)].

Orthostatic Hypotension

Advise patients and caregivers that DANYELZA can cause severe low blood pressure when standing after sitting or lying down. Advise patients and caregivers to report any signs or symptoms, such as dizziness, lightheadedness or fainting during treatment with DANYELZA [see Warnings and Precautions (5.5)].

Embryo-Fetal Toxicity[see Warnings and Precautions (5.6)and Use in Specific Populations (8.1, 8.3)] .

Advise females of reproductive potential, including pregnant women, of the potential risk to the fetus.

Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective contraception during treatment with and for 2 months after the last dose of DANYELZA.

Lactation

Advise women not to breastfeed during treatment with DANYELZA and for 2 months after the last dose [see Use in Specific Populations (8.2)].

Manufactured by:
BTG International Inc.

West Conshohocken, PA 19428
US License No. 1861

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).

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 (2.4and 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/m ²/day by subcutaneous injection, beginning 5 days prior to DANYELZA infusion.
• Days 1 to 5: administer GM-CSF 500 µg/m ²/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/m 2/day					500 µg/m 2/day
Intravenous DANYELZA							3 mg/kg/day		3 mg/kg/day		3 mg/kg/day

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

• 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 150	> 30 to 37.5	20	100	1.2 to 1.5

If not used immediately, store the diluted DANYELZA infusion solution at room temperature (15°C to 25°C [59°F to 77°F]) 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.

• 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.

Injection: 40 mg/10 mL (4 mg/mL) clear to slightly opalescent and colorless to slightly yellow solution in a single-dose vial.

DANYELZA is contraindicated in patients with a history of severe hypersensitivity reaction to naxitamab-gqgk. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)].

DANYELZA can cause serious infusion reactions requiring urgent intervention including fluid resuscitation, administration of bronchodilators and corticosteroids, intensive care unit admission, infusion rate reduction or interruption of DANYELZA infusion. Infusion-related reactions included hypotension, bronchospasm, hypoxia, and stridor [see Adverse Reactions (6.1)].

Serious infusion-related reactions occurred in 4% of patients in Study 201 and in 18% of patients in Study 12-230. Infusion-related reactions of any Grade occurred in 100% of patients in Study 201 and 94% of patients in Study 12-230. Hypotension of any grade occurred in 100% of patients in Study 201 and 89% of patients in Study 12-230.

In Study 201, 68% of patients experienced Grade 3 or 4 infusion reactions; and in Study 12-230, 32% of patients experienced Grade 3 or 4 infusion reactions. Anaphylaxis occurred in 12% of patients and 2 patients (8%) permanently discontinued DANYELZA due to anaphylaxis in Study 201. One patient in Study 12-230 (1.4%) experienced a Grade 4 cardiac arrest 1.5 hours following completion of DANYELZA infusion.

In Study 201, infusion reactions generally occurred within 24 hours of completing a DANYELZA infusion, most often within 30 minutes of initiation. Infusion reactions were most frequent during the first infusion of DANYELZA in each cycle. Eighty percent of patients required reduction in infusion rate and 80% of patients had an infusion interrupted for at least one infusion-related reaction.

Caution is advised in patients with pre-existing cardiac disease, as this may exacerbate the risk of severe hypotension.

Premedicate with an antihistamine, acetaminophen, an H2 antagonist and corticosteroid as recommended [see Dosage and Administration (2.2)]. Monitor patients closely for signs and symptoms of infusion reactions during and for at least 2 hours following completion of each DANYELZA infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity and institute appropriate medical management as needed [see Dosage and Administration (2.3)and Contraindications (4)].

DANYELZA can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome.

Myocarditis has occurred in adolescent patients receiving DANYELZA in clinical trials and expanded access programs. Myocarditis occurred within days of receiving DANYELZA requiring drug interruption. Monitor for signs and symptoms of myocarditis during treatment with DANYELZA. Withhold, reduce the dose, or permanently discontinue DANYELZA based on severity [see Dosage and Administration (2.3)].

Hypertension occurred in 44% of patients in Study 201 and 28% of patients in Study 12-230 who received DANYELZA. Grade 3 or 4 hypertension occurred in 4% of patients in Study 201 and 7% of patients in Study 12-230. Four patients (6%) in Study 12-230 permanently discontinued DANYELZA due to hypertension. In both studies, most events occurred on the day of DANYELZA infusion and occurred up to 9 days following an infusion of DANYELZA.

Do not initiate DANYELZA in patients with uncontrolled hypertension. Monitor blood pressure during infusion, and at least daily on Days 1 to 8 of each cycle of DANYELZA and evaluate for complications of hypertension including RPLS [see Warnings and Precautions (5.2)] . Interrupt DANYELZA infusion and resume at a reduced rate, or permanently discontinue DANYELZA based on the severity [see Dosage and Administration (2.3)and Adverse Reactions (6.1)] .

Orthostatic hypotension has occurred in patients receiving DANYELZA in clinical trials and expanded access programs. Severe orthostatic hypotension, including cases requiring hospitalization, have occurred. Cases occurred within hours to 6 days of DANYELZA infusions in any cycle.

In patients with symptoms of orthostatic hypotension, monitor postural blood pressure prior to initiating treatment with DANYELZA and as clinically indicated with subsequent dosing. Withhold, reduce dose, or permanently discontinue DANYELZA based on severity [ see Dosage and Administration (2.3)].

Based on its mechanism of action, DANYELZA may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential, including pregnant women, of the potential risk to a fetus. Advise females of reproductive potential to use effective contraceptive during treatment with DANYELZA and for two months after the last dose. [see Use in Specific Populations (8.1, 8.3)] .

The following clinically significant adverse reactions are also described elsewhere in the labeling:

• Serious Infusion-Related Reactions [see Warnings and Precautions (5.1)]
• Neurotoxicity [see Warnings and Precautions (5.2)]
• Myocarditis [see Warnings and Precautions (5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Orthostatic Hypotension [see Warnings and Precautions (5.5)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of DANYELZA in combination with GM-CSF was evaluated in patients with refractory or relapsed high-risk neuroblastoma in bone or bone marrow who had demonstrated a partial response, minor response, or stable disease following initial or subsequent therapy, and in patients who were in second complete remission, from two open-label, single arm studies, Study 201 (n=25) and Study 12-230 (n=72). Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (Day 1, 3 and 5) in the first week of each cycle. Patients also received GM-CSF 250 µg/m ²/day subcutaneously on Days -4 to 0 and GM-CSF 500 µg/m ²/day subcutaneously on Days 1 to 5 [see Clinical Studies (14)].

The most common adverse reactions in Studies 201 and 12-230 (≥25% in either study) were infusion-related reaction, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema and irritability. The most common Grade 3 or 4 laboratory abnormalities (≥5% in either study) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium and decreased phosphate.

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of anti-drug antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of anti-drug antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies or to other naxitamab products may be misleading.

In Study 201, 2 of 24 (8%) patients tested positive for anti-drug antibodies (ADA) after treatment with DANYELZA.

In Study 12-230, 27 of 117 patients (23%) tested positive for ADA after treatment with DANYELZA by an assay that was not fully validated; therefore, the incidence of ADA may not be reliable.

The following adverse reactions have been identified during expanded access and post-approval use of DANYELZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Neurological:Orthostatic hypotension, Transverse myelitis

Cardiac disorders:Myocarditis

DANYELZA may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

The safety and effectiveness of DANYELZA, in combination with GM-CSF for the treatment of relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response or stable disease following prior therapy, have been established in pediatric patients 1 year of age and older.

Safety and effectiveness have not been established in pediatric patients younger than 1 year of age.

Neuroblastoma is largely a disease of pediatric and young adult patients. Clinical studies of DANYELZA in combination with GM-CSF did not include patients 65 years of age and older.

Naxitamab-gqgk is a glycolipid disialoganglioside (GD2)-binding recombinant humanized monoclonal IgG1 antibody, that contains human framework regions and murine complementarity-determining regions. Naxitamab-gqgk is produced in a Chinese hamster ovary cell line and has an approximate molecular weight of 144 kDa without glycosylation.

DANYELZA (naxitamab-gqgk) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution for intravenous infusion. Each single-dose vial contains 40 mg of naxitamab-gqgk in 10 mL of solution. Each mL of solution contains 4 mg of naxitamab-gqgk, and citric acid anhydrous (0.71 mg), poloxamer 188 (1.5 mg), sodium chloride (7.01 mg), sodium citrate (6.3 mg), and Water for Injection, USP. The pH is approximately 5.7.

Naxitamab-gqgk binds to the glycolipid GD2. GD2 is a disialoganglioside that is overexpressed on neuroblastoma cells and other cells of neuroectodermal origin, including the central nervous system and peripheral nerves. In vitro, naxitamab-gqgk was able to bind to cell surface GD2 and induce complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC).

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of naxitamab-gqgk have not been fully characterized.

The geometric mean (CV%) maximum plasma concentration (C _max) of naxitamab-gqgk was 57.4 µg/mL (49%) following DANYELZA 3 mg/kg intravenous infusion over 30 minutes.

No animal studies have been conducted to evaluate the carcinogenic or mutagenic potential of naxitamab-gqgk.

Dedicated studies evaluating the effects of naxitamab-gqgk on fertility in animals have not been conducted.

Non-clinical studies suggest that naxitamab-gqgk-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of immune-mediated cytotoxic activity.

In a nude rat model, slight-moderate hyperplasia and erosion of the glandular mucosa of the stomach occurred, occasionally accompanied by diffuse inflammation. Complete recovery of all histopathological findings in the stomachs of male rats was observed; however, only partial recovery was observed in the stomachs of female rats during the four week off-drug period.

The efficacy of DANYELZA in combination with GM-CSF was evaluated in two open-label, single arm trials in patients with high-risk neuroblastoma with refractory or relapsed disease in the bone or bone marrow, Study 201 and Study 12-230.

DANYELZA (naxitamab-gqgk) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution for intravenous infusion supplied as a carton containing one 40 mg/10 mL (4 mg/mL) single-dose vial.

NDC 50633-230-01

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.

Advise the patient and caregiver to read the FDA-approved patient labeling (Patient Information).

NDC 50633-230-01

DANYELZA ^®
(naxitamab-gqgk)
Injection

40 mg/10 mL
(4 mg/mL)

Rx ONLY

For intravenous
infusion after dilution

Single-dose vial

Discard unused portion

No preservative

SERB
Pharmaceuticals

Principal Display Panel (10 mL Vial Carton)