Posology : מינונים

2           DOSAGE AND ADMINISTRATION
2.1 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.

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
250 µg/m2/day                 500 µg/m2/day
GM-CSF
Intravenous                                    3                 3                                 3 DANYELZA                                     mg/kg/           mg/kg/                             mg/kg/ day               day                               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).


2.2 Premedications and Supportive Medications
Pain Management Prior to and During Infusion [see Warnings and Precautions (6.2)]: • 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 (6.1) and Adverse Reactions (7.1)].
• 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.
2.3 Dosage Modifications for Adverse Reactions
The recommended dosage modifications for DANYELZA for adverse reactions are presented in Table 2.

Table 2. Recommended DANYELZA Dosage Modifications for Adverse Reactions Adverse Reaction        Severity1                             Dosage Modifications Infusion-related        Grade 2                               • Reduce DANYELZA infusion rate to reactions [see Warnings Defined as:                              50% of previous rate and monitor and Precautions (6.1)]  Therapy or infusion interruption         closely until recovery to Grade ≤ 1 indicated but responds promptly to    • Increase infusion rate gradually to rate symptomatic treatment (e.g.,             prior to the event as tolerated antihistamines, NSAIDS, narcotics, IV
fluids); prophylactic medications indicated for ≤24 hours
Grade 3                                    •   Immediately interrupt DANYELZA Defined as:                                    infusion and monitor closely until Prolonged (e.g., not rapidly responsive        recovery to Grade ≤ 2 to symptomatic medication and/or brief     •   Resume infusion at 50% of the rate interruption of infusion); recurrence of       prior to the event and increase infusion symptoms following initial                     rate gradually to infusion rate prior to improvement; hospitalization indicated         the event as tolerated.
for clinical sequelae                      •   Permanently discontinue DANYELZA in patients not responding to medical intervention.
Grade 4 infusion-related reactions         •   Permanently discontinue DANYELZA Defined as:
Life-threatening consequences: urgent intervention indicated or
Grade 3 or 4 anaphylaxis
Pain [see Warnings and    Grade 3 unresponsive to maximum            •   Permanently discontinue DANYELZA Precautions (6.2)]        supportive measures
Reversible posterior      All Grades                                 •   Permanently discontinue DANYELZA leukoencephalopathy syndrome (RPLS) [see
Warnings and
Precautions (6.2)]
Transverse myelitis       All Grades                                 •   Permanently discontinue DANYELZA [see Warnings and
Precautions (6.2)]
Peripheral neuropathy     Motor neuropathy: Grade 2 or greater       •   Permanently discontinue DANYELZA [see Warnings and         or
Precautions (6.2)]        Sensory neuropathy: Grade 3 or 4
Neurological disorders    Grade 2 to 4 resulting in decreased        •   Withhold DANYELZA until resolution of the eye [see           visual acuity or limiting activities of    •   If resolved resume DANYELZA at Warnings and              daily living                                   50% of the prior dose; if tolerated Precautions (6.2)]                                                       without recurrence of symptoms, gradually increase DANYELZA to dose prior to onset of symptoms
•   Permanently discontinue DANYELZA if not resolved within 2 weeks or upon recurrence
Subtotal or total vision loss              •   Permanently discontinue DANYELZA Prolonged urinary         Persisting following discontinuation of    •   Permanently discontinue DANYELZA retention [see Warnings   opioids and Precautions (6.2)]
Hypertension              Grade 3                                    •   Withhold DANYELZA or pause [see Warnings and                                                        infusion until recovery to ≤ Grade 2 Precautions (6.3)]                                                   •   Resume infusion at 50% of prior rate; if tolerated without recurrence of symptoms, gradually increase
DANYELZA to rate prior to onset of symptoms
•   Permanently discontinue DANYELZA in patients not responding to medical intervention
Grade 4                                    •   Permanently discontinue DANYELZA Other Adverse            Grade 3                                    •   Withhold DANYELZA until recovery Reactions [see Adverse                                                  to Grade ≤ 2 Reactions (7.1)]                                                    •   If resolved to Grade ≤ 2 resume DANYELZA at same rate
•   Permanently discontinue DANYELZA if not resolved to Grade ≤2 within 2 weeks
Grade 4                                    •   Permanently discontinue DANYELZA 1
Based on Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 
2.4 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.

Table 3. Preparation of DANYELZA, 4 mg/ml

Final
Total infusion volume
Volume of 5%                                  concentration of
DANYELZA           DANYELZA                               achieved by adding Albumin                                       prepared dose               volume                                 sufficient 0.9% Sodium (Human), USP                                  DANYELZA
(mg)               (mL)                                   Chloride Injection, (mL)                                          infusion
USP (mL)
(mg/mL)
≤ 80               ≤ 20                 10                50                          ≤ 1.6 81 to 120          > 20 to 30           15                75                          1.1 to 1.6 121 to 160         > 30 to 40           20                100                         1.2 to 1.6 161 to 200         > 40 to 50           25                125                         1.3 to 1.6 201 to 240         > 50 to 60           30                150                         1.3 to 1.6
241 to 280         > 60 to 70           35                175                         1.4 to 1.6

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


2.5 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.