Dosage & Administration
The recommended dosage of DANYELZA is 3 mg/kg/day (up to 150 mg/day), administered as an intravenous infusion after dilution on Days 1, 3, and 5 of each treatment cycle. 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 GM-CSF subcutaneously prior to and during each treatment cycle as recommended.
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Danyelza Prescribing Information
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)].
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).
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.
| 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).
Premedications and Supportive Medications
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.
Dosage Modifications for Adverse Reactions
The recommended dosage modifications for DANYELZA for adverse reactions are presented in Table 2.
| 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 |
|
| 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 |
| |
| Grade 4 infusion-related reactions Defined as: Life-threatening consequences: urgent intervention indicated or Grade 3 or 4 anaphylaxis |
| |
| Pain [see Warnings and Precautions (5.2)] | Grade 3 unresponsive to maximum supportive measures |
|
| Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.2)] | All Grades |
|
| Transverse myelitis [see Warnings and Precautions (5.2)] | All Grades |
|
| Peripheral neuropathy [see Warnings and Precautions (5.2)] | Motor neuropathy: Grade 2 or greater or Sensory neuropathy: Grade 3 or 4 |
|
| 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 |
|
| Subtotal or total vision loss |
| |
| Prolonged urinary retention [see Warnings and Precautions (5.2)] | Persisting following discontinuation of opioids |
|
| Myocarditis [see Warnings and Precautions (5.3)] | Grade 2 or 3 |
|
| Grade 4 |
| |
| Hypertension [see Warnings and Precautions (5.4)] | Grade 3 |
|
| Grade 4 |
| |
| Orthostatic hypotension [see Warnings and precautions (5.5)] | All grades |
|
| Other Adverse Reactions [see Adverse Reactions (6.1)] | Grade 3 |
|
| Grade 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.
| 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 40 | 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.
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.
Injection: 40 mg/10 mL (4 mg/mL) clear to slightly opalescent and colorless to slightly yellow solution in a singledose vial.
Pregnancy
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.
Lactation
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.
Females and Males of Reproductive Potential
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 last dose of DANYELZA.
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.
Geriatric Use
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.
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)].