Dosing and uses of Unituxin (dinutuximab)
Adult dosage forms and strengths
Not indicated
Pediatric dosage forms and strengths
solution for injection
- 17.5mg/5mL (3.5mg/mL)
Neuroblastoma
Indicated in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA) for pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-time multiagent, multimodality therapy
17.5 mg/m²/day IV over 10-20 hr for 4 consecutive days for maximum of 5 cycles
Cycles 1, 3, and 5 (24 days' duration): Administer dinutuximab on days 4, 5, 6, and 7
Cycles 2 and 4 (32 days' duration): Administer dinutuximab on days 8, 9, 10, and 11
Initiate at infusion rate of 0.875 mg/m²/hr for 30 min; may gradually increase infusion rate, as tolerated, to maximum of 1.75 mg/m²/hr
Administration
Verify that patient has adequate hematologic, respiratory, hepatic, and renal function prior to initiating each course of dinutuximaB
Not for administration as intravenous push or bolus
Pretreatment and guidelines for pain management
- Intravenous hydration
- Administer 0.9% NaCl injection, USP 10 mL/kg intravenous infusion over 1 hr just prior to initiating each dinutuximab infusion
- Analgesics
- Morphine sulfate (50 mcg/kg) IV immediately prior to initiation of dinutuximab; continue as drip at infusion rate of 20-50 mcg/kg/hr during and for 2 hr following completion of dinutuximab
- Administer additional 25-50 mg/kg IV morphine sulfate doses PRN for pain up to once q2hr followed by increase in morphine sulfate infusion rate in clinically stable patients
- May use fentanyl or hydromorphone if morphine sulfate not tolerated
- If pain inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with intravenous morphine
- Antihistamines and antipyretics
- Administer antihistamine such as diphenhydramine (0.5-1 mg/kg; not to exceed 50 mg) IV over 10-15 min starting 20 min prior to initiation of dinutuximab and as tolerated q4-6hr during dinutuximab infusion
- Administer acetaminophen (10-15 mg/kg; not to exceed 650 mg) 20 min prior to each dinutuximab infusion and q4-6hr PRN for fever or pain; administer ibuprofen (5-10 mg/kg) q6hr PRN for control of persistent fever or pain
Dosage modifications
Adverse reactions requiring permanent therapy discontinuation
- 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 peripheral motor neuropathy
- Subtotal or total vision loss
- Grade 4 hyponatremia despite appropriate fluid management
Dose modifications for selected adverse reactions
- Mild-to-moderate adverse reactions include transient rash, fever, rigors, and localized urticaria
- Onset of reaction: Reduce infusion rate to 50% of previous rate; monitor closely
- After resolution: Gradually increase infusion rate up to maximum rate of 1.75 mg/m²/hr
- Prolonged or severe adverse reactions including mild bronchospasm without other symptoms or angioedema that does not affect airway
- Onset of reaction: Interrupt therapy immediately
- After resolution: Resume dinutuximab at 50% of previous rate and monitor if signs and symptoms resolve rapidly
- First recurrence
- Discontinue therapy until following day; if symptoms resolve and continued therapy necessary, premedicate with hydrocortisone 1 mg/kg (maximum dose 50 mg) IV and administer dinutuximab at rate of 0.875 mg/m²/hr in an intensive care unit
- Second recurrence
- Permanently discontinue therapy
Capillary leak syndrome
- Moderate-to-severe but not life-threatening capillary leak syndrome
- Onset of reaction: Interrupt therapy immediately
- After resolution: Resume dinutuximab infusion at 50% of previous rate
- Life-threatening capillary leak syndrome
- Onset of action: Discontinue therapy for current cycle
- After resolution: In subsequent cycles, administer dinutuximab infusion at 50% of previous rate
Hypotension requiring medical intervention
- Symptomatic hypotension, systolic blood pressure (SBP) less than lower limit of normal for age, or SBP decreased by more than 15% compared with baseline
- Onset of reaction: Interrupt therapy immediately
- After resolution: Resume dinutuximab infusion at 50% of previous rate; if blood pressure remains stable for at least 12 hr, increase infusion rate as tolerated to maximum rate of 1.75 mg/m²/hr
Severe systemic infection or sepsis
- Onset of reaction: Discontinue dinutuximab until resolution of infection and proceed with subsequent cycles of therapy
Neurological disorder of the eye
- Onset of reaction: Discontinue dinutuximab infusion until resolution
- After resolution: Reduce dinutuximab dose by 50%
- First recurrence or if accompanied by visual impairment: Permanently discontinue therapy
Unituxin (dinutuximab) adverse (side) effects
>10% (All Grades)
Dinutuximab/retinoic acid group
Pain (85%)
Pyrexia (72%)
Edema (17%)
Thrombocytopenia (66%)
Lymphopenia (62%)
Anemia (51%)
Neutropenia (39%)
Hypotension (60%)
Capillary leak syndrome (40%)
Hemorrhage (17%)
Hypertension (14%)
Hyponatremia (58%)
Hypokalemia (43%)
Hypoalbuminemia (33%)
Hypocalcemia (27%)
Hypophosphatemia (20%)
Hyperglycemia (18%)
Hypertriglyceridemia (16%)
Decreased appetite (15%)
Hypomagnesemia (12%)
Increased alanine aminotransferase (56%)
Increased aspartate aminotransferase (28%)
Increased serum creatinine (15%)
Increased weight (10%)
Vomiting (46%)
Diarrhea (43%)
Nausea (10%)
Urticaria (37%)
Hypoxia (24%)
Tachycardia (19%)
Sepsis (18%)
Device-related infection (16%)
Proteinuria (16%)
Peripheral neuropathy (13%)
Warnings
Black Box Warning
Infusion reactions
- Serious and potentially life-threatening infusion reactions occurred in 26% of patients
- Administer required prehydration and premedication, including antihistamines, prior to each dinutuximab infusion
- Monitor closely for signs and symptoms of an infusion reaction during and for at least 4 hr following completion of each dinutuximab infusion
- Immediately interrupt therapy for severe infusion reactions and permanently discontinue dinutuximab for anaphylaxis
Neuropathy
- Causes severe neuropathic pain in the majority of patients
- Administer intravenous opioid prior to, during, and for 2 hr following completion of the infusion
- In clinical studies of patients with high-risk neuroblastoma, grade 3 peripheral sensory neuropathy occurred in 2-9% of patients
- In clinical studies of dinutuximab and related GD2-binding antibodies, severe motor neuropathy was observed in adults
- Resolution of motor neuropathy was not documented in all cases
- Discontinue for severe unresponsive pain, severe sensory neuropathy, or moderate-to-severe peripheral motor neuropathy
Contraindications
Hypersensitivity
Cautions
Infusion reactions may occur; prior to dinutuximab infusion, administer required intravenous hydration and premedication with antihistamines, analgesics, and antipyretics and monitor for signs and symptoms of infusion reactions during and for at least 4 hr following completion of each infusion in a setting where cardiopulmonary resuscitation medication and equipment is available
Abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal pain, and arthralgia reported in dinutuximab/retinoic acid treated group; premdicate with analgesics, including IV opioids, prior to each dose of dinutuximab and continue until 2 hr following completion of dinutuximab; for severe pain, decrease dinutuximab infusion rate to 0.875 mg/m²/hr; discontinue therapy if pain is not adequately controlled despite infusion rate reduction and institution of maximum supportive measures
Permanently discontinue therapy in patients with grade 2 peripheral motor neuropathy, grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks, or grade 4 sensory neuropathy
Immediately interrupt or discontinue therapy and institute supportive management in patients with symptomatic or severe capillary leak syndrome
Closely monitor blood pressure during treatment; immediately interrupt or discontinue therapy and institute supportive management in patients with symptomatic hypotension, systolic blood pressure less than lower limit of normal for age, or systemic blood pressure that is decreased by more than 15% compared with baseline
Monitor patients for signs and symptoms of systemic infection and temporarily discontinue therapy in patients who develop systemic infection until resolution of infection
Interrupt therapy in patients experiencing dilated pupil with sluggish light reflex or other visual disturbances that do not cause visual loss; upon resolution and if continued treatment with therapy is necessary, decrease dinutuximab dose by 50%; permanently discontinue therapy in patients with recurrent signs of eye disorder following dose reduction and patients who experience vision loss
Bone marrow suppression reported; monitor peripheral blood cell counts closely during therapy
Electrolyte abnormalities reported; monitor serum electrolytes daily during therapy
Atypical hemolytic uremic syndrome reported; permanently discontinue therapy and institute supportive management for signs of the syndrome
Advise pregnant women of the potential risk to a fetus; advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of dinutuximaB
Pregnancy and lactation
Pregnancy: Studies in pregnant women and reproductive studies in animals have not been performed; monoclonal antibodies are transported across 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; advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of dinutuximaB
Lactation: Unknown whether distributed in breast milk; potential for serious adverse reactions in a breastfed infant; advise nursing mother to discontinue breastfeeding during therapy
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Unituxin (dinutuximab)
Mechanism of action
Chimetic monoclonal antibody that binds to the glycolipid disialoganglioside (GD2). GD2 is a glycolipid expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including central nervous system and peripheral nerves
Dinutuximab binds to cell surface GD2 and induces lysis of GD2-expressing cells through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity
Absorption
Peak plasma concentration: 11.5 mcg/mL
Distribution
Vd: 5.4 L
Elimination
Half-life: 10 days
Administration
IV Preparation
Inspect visually for particulate matter and discoloration prior to administration
Discard the vial if the solution is cloudy, has pronounced discoloration, or contains particulate matter
Aseptically withdraw the required volume of dinutuximab from the single-use vial and inject into a 100 mL bag of 0.9% NaCl injection, USp
Mix by gentle inversion; do NOT shake
Discard unused contents of the viaL
Storage
Store vials under refrigeration at 2-8°C until time of use
Do not freeze or shake the viaL
Keep vial in outer carton to protect from light
