Usual Pediatric Dose for Neuroblastoma

17.5 mg/m2/day IV over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles:

• Infuse on days 4, 5, 6, and 7 during cycles 1, 3, and 5 (cycles 1, 3, and 5 are 24 days in duration).
• Infuse on days 8, 9, 10, and 11 during cycles 2 and 4 (cycles 2 and 4 are 32 days in duration).

• Initiate at 0.875 mg/m2/hour for 30 minutes. Gradually increase as tolerated to a maximum rate of 1.75 mg/m2/hour.

• Administer 0.9% sodium chloride 10 mL/kg IV over one hour just prior to initiating each infusion.

• Administer morphine 50 mcg/kg IV immediately prior to infusion and then continue as a morphine drip at an infusion rate of 20 to 50 mcg/kg/hour during and for 2 hours following completion of therapy.
• Administer additional 25 mcg/kg to 50 mcg/kg IV doses of morphine as needed for pain up to once every 2 hours followed by an increase in the morphine infusion rate in stable patients.
• Consider using fentanyl or hydromorphone if morphine is not tolerated.
• If pain is inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with IV morphine.

• Administer an antihistamine such as diphenhydramine (0.5 to 1 mg/kg; maximum dose 50 mg) IV over 10 to 15 minutes starting 20 minutes prior to initiation of therapy and as tolerated every 4 to 6 hours during therapy.
• Administer acetaminophen (10 to 15 mg/kg; maximum dose 650 mg) 20 minutes prior to each infusion and every 4 to 6 hours as needed for fever or pain. -Administer ibuprofen (5 to 10 mg/kg) every 6 hours as needed for control of persistent fever or pain.

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Data not available

Dose Adjustments

Permanently discontinue therapy for:

• Grade 3 or 4 anaphylaxis
• Grade 3 or 4 serum sickness
• Grade 3 pain unresponsive to maximum supportive measures
• Grade 4 sensory neuropathy or Grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks
• Grade 2 or greater peripheral motor neuropathy
• Urinary retention that persists following discontinuation of opioids
• Transverse myelitis
• Reversible posterior leukoencephalopathy syndrome (RPLS)
• Subtotal or total vision loss
• Grade 4 hyponatremia despite appropriate fluid management

• Mild to moderate reaction (e.g., transient rash, fever, rigors, and localized urticaria that respond promptly to symptomatic treatment): Reduce infusion rate by 50%; monitor closely. Upon resolution, gradually increase infusion rate up to a maximum of 1.75 mg/m2/hour.
• Severe or prolonged reaction (e.g., mild bronchospasm without other symptoms, angioedema that does not affect the airway): Interrupt infusion; if symptoms resolve rapidly, resume infusion at 50% of the previous rate and monitor closely. If reaction recurs, discontinue therapy until the following day. If symptoms resolve and further treatment is warranted, premedicate with IV hydrocortisone 1 mg/kg (maximum 50 mg) and infuse at a rate of 0.875 mg/m2/hour in an intensive care unit. If reaction recurs a second time, permanently discontinue therapy.

• Onset of reaction: Discontinue the infusion until resolved; upon resolution, reduce the dose by 50%.
• First recurrence or if accompanied by visual impairment: Permanently discontinue therapy.

• Moderate to severe, but not life-threatening: Interrupt infusion; upon resolution, resume infusion at 50% of the previous rate.
• Life-threatening: Discontinue infusion for the current cycle; in subsequent cycles, infuse at 50% of the previous rate. If life-threatening capillary leak syndrome recurs, permanently discontinue therapy.

• Permanently discontinue therapy and administer supportive management.

• Permanently discontinue therapy.

• Interrupt infusion; upon resolution, resume infusion at 50% of the previous rate. If blood pressure remains stable for 2 hours or more, increase infusion rate as tolerated up to a maximum rate of 1.75 mg/m2/hour.

• Discontinue therapy until infection resolves; may resume therapy with subsequent cycles.

Precautions

US BOXED WARNINGS:
Infusion Reactions:

• Serious and potentially life-threatening infusion reactions occurred in 26% of patients. Administer prehydration and premedication including antihistamines prior to each infusion. Monitor patients for infusion reactions during and for at least 4 hours following completion of each infusion. Immediately interrupt therapy for severe infusion reactions and permanently discontinue therapy for anaphylaxis.

• This drug causes serious neurologic adverse reactions including severe neuropathic pain and peripheral neuropathy. Severe neuropathic pain occurs in most patients. Administer IV opioid prior to, during, and for 2 hours following completion of the infusion.
• In clinical studies of patients with high-risk neuroblastoma, Grade 3 peripheral sensory neuropathy occurred in 2% to 9% of patients. In clinical studies of this drug and related GD2-binding antibodies, severe motor neuropathy has occurred. Resolution of motor neuropathy did not occur in all cases. Discontinue this drug for severe unresponsive pain, severe sensory neuropathy, and moderate to severe peripheral motor neuropathy

Dialysis

Data not available

Other Comments

Administration advice:

• Verify that patients have adequate hematologic, respiratory, hepatic, and renal function prior to initiating each course of therapy.
• Administer required premedication and hydration prior to initiation of each course of therapy.

• Store vials under refrigeration at 2°C to 8°C until time of use. Do not freeze.
• Do not shake the vial.
• Keep the vial in the outer carton in order to protect from light.

• Refer to manufacturer product information.

• The risk of serious infusion reactions and anaphylaxis and to immediately report any signs, such as facial or lip swelling, urticaria, difficulty breathing, lightheadedness, or dizziness that occur during or within 24 hours following the infusion.
• The risk of severe pain and peripheral sensory and motor neuropathy and to promptly report severe or worsening pain and signs of neuropathy such as numbness, tingling, burning, or weakness.
• The risk of capillary leak syndrome and to immediately report any signs or symptoms.
• The risk of hypotension during the infusion and to immediately report any signs or symptoms.
• The risk of infection following treatment and to immediately report any signs or symptoms.
• The risk of neurological disorders of the eye and to promptly report signs or symptoms such as blurred vision, photophobia, ptosis, diplopia, or unequal pupil size.
• The risk of bone marrow suppression, and to promptly report signs or symptoms of anemia, thrombocytopenia, or infection.
• The risk of electrolyte abnormalities including hypokalemia, hyponatremia, and hypocalcemia, and to report any signs or symptoms such as seizures, heart palpitations, and muscle cramping.
• The risk of hemolytic uremic syndrome and to report any signs or symptoms such as fatigue, dizziness, fainting, pallor, edema, decreased urine output, or hematuria.
• The potential risk to the fetus if administered during pregnancy (for women of reproductive potential) and the need for use of effective contraception during and for at least two months after completing therapy.