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

5.1 Serious Infusion-Related Reactions

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.

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)].

5.2 Neurotoxicity

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

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)].

5.3 Hypertension

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)].

5.4 Embryo-Fetal Toxicity

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 final 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)]
• Hypertension [see Warnings and Precautions (5.3)]

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/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 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.

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:

^* 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).

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:

^* 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.

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:

^* 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).

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 from expanded access reports with 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: Transverse myelitis

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 final dose of DANYELZA.

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

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 final dose of DANYELZA.

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.