6 ADVERSE REACTIONS

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)]

6.1 Clinical Trials Experience

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 highrisk 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/m2/day subcutaneously on Days -4 to 0 and GM-CSF 500 μg/m2/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.

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
Adverse Reaction	DANYELZA with GM-CSF* (n=25)
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
Body system
* Adverse reactions were graded using CTCAE version 4.0. † Pain includes pain, abdominal pain, pain in extremity, bone pain, neck pain, back pain, and musculoskeletal pain. ‡ 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. § Fatigue includes fatigue, asthenia. ¶ Pyrexia not occurring on the day of infusion or the day following an infusion # Urticaria, not occurring on the day of infusion or the day following an infusion Þ Tachycardia includes sinus tachycardia and tachycardia ß Peripheral neuropathy includes peripheral sensory neuropathy, paresthesia, neuralgia. à Neurological disorders of the eye includes unequal pupils, blurred vision, and mydriasis.
General disorders and administration site conditions
Pain†	100	72
Infusion-related reaction‡	100	68
Edema	28	0
Fatigue§	28	0
Pyrexia¶	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#	32	4
Cardiac disorders
TachycardiaÞ	84	4
Nervous system disorders
Peripheral neuropathyß	32	0
Headache	28	8
Depressed level of consciousness	24	16
Eye disorders
Neurological disorders of the eyeà	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* n=25
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)
* 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 onstudy laboratory measurement (range: 23 to 24 patients).
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*,† (n=72)
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
Body system
* 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. ‡ 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. § Pain includes pain, abdominal pain, pain in extremity, bone pain, neck pain, back pain, non-cardiac chest pain, flank pain, and musculoskeletal pain. ¶ Fatigue includes fatigue, asthenia. # Pyrexia not occurring on the day of infusion or the day following an infusion. Þ Peripheral neuropathy includes peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, neuralgia. ß Neurological disorders of the eye includes unequal pupils, blurred vision, accommodation disorder, visual impairment and photophobia.
General disorders and administration site conditions
Infusion-related reaction‡	94	32
Pain§	94	2.8
Fatigue¶	44	0
Injection site reaction	28	0
Localized edema	25	0
Pyrexia#	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 neuropathyÞ	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 ß	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
	DANYELZA with GM-CSF* n=72
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)
* 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).
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

6.2 Immunogenicity

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.

6.3 Postmarketing Experience/Spontaneous Reports

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