Danyelza Drug Information

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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

• Premedications and Supportive Medications Pain Management Prior to and During Infusion: 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. 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.

Dosage Modifications for Adverse Reactions

The recommended dosage modifications for DANYELZA for adverse reactions are presented in Table 2. Table 2. Recommended DANYELZA Reversible posterior leukoencephalopathy syndrome (RPLS)

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

Administration Administer

DANYELZA as a diluted intravenous infusion as recommended. Do not administer DANYELZA as an intravenous push or bolus. 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. Observe patients for a minimum of 2 hours following each infusion.

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

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 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.

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

Pregnancy Risk Summary Based on its mechanism of action, DANYELZA may cause fetal harm when administered to pregnant women. 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 respectively.

Pediatric Use 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.

DANYELZA is contraindicated in patients with a history of severe hypersensitivity reaction to naxitamab-gqgk. Reactions have included anaphylaxis.