Dosing & Uses
Not indicated
Dosage Forms & 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-day duration): Administer on days 4, 5, 6, and 7
Cycles 2 and 4 (32-day duration): Administer on days 8, 9, 10, and 11
Dosage Modifications
Renal and hepatic impairment: Not studied
Adverse reactions requiring permanent 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 >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 H4
-
Mild-to-moderate adverse reactions
- Examples: Transient rash, fever, rigors, localized urticaria
- Onset of reaction: Reduce at 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
- Examples: Mild bronchospasm without other symptoms or angioedema that does not affect airway
- Onset of reaction: Interrupt therapy immediately
- After resolution: Resume 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
Capillary leak syndrome
-
Moderate-to-severe but not life-threatening capillary leak syndrome
- Onset of reaction: Interrupt therapy immediately
- After resolution: Resume at 50% of previous rate
-
Life-threatening
- Onset of action: Discontinue therapy for current cycle
- After resolution: In subsequent cycles, resume at 50% of previous rate
- First recurrence: Permanently discontinue
Hypotension requiring medical intervention
- Symptomatic hypotension, systolic blood pressure (SBP)
15% compared with baseline - Onset of reaction: Interrupt therapy immediately
- After resolution: Resume 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 until infection resolves and proceed with subsequent cycles
Neurological disorder of the eye
- Onset of reaction: Discontinue until resolution
- After resolution: Reduce dose by 50%
- First recurrence or if accompanied by visual impairment: Permanently discontinue
Adverse Effects
>10%
All grades (dinutuximab/RA)
- Pain (85%)
- Thrombocytopenia (66%)
- Lymphopenia (62%)
- Infusion reactions (60%)
- Hypotension (60%)
- Hyponatremia (58%)
- Increased ALT (56%)
- Anemia (51%)
- Vomiting (46%)
- Hypokalemia (43%)
- Diarrhea (43%)
- Capillary leak syndrome (40%)
- Neutropenia (39%)
- Urticaria (37%)
- Hypoalbuminemia (33%)
- Increased AST (28%)
- Hypocalcemia (27%)
- Hypoxia (24%)
- Hypophosphatemia (20%)
- Tachycardia (19%)
- Hyperglycemia (18%)
- Sepsis (18%)
- Pyrexia (17%)
- Hemorrhage (17%)
- Hypertriglyceridemia (16%)
- Device related infection (16%)
- Proteinuria (16%)
- Increased serum creatinine (15%)
- Decreased appetite (15%)
- Hypertension (14%)
- Peripheral neuropathy (13%)
- Hypomagnesemia (12%)
All grades (dinutuximab/GM-CSF)
- Pain (77%)
- Thrombocytopenia (62%)
- Pyrexia (55%)
- Lymphopenia (54%)
- Infusion reactions (47%)
- Hypotension (43%)
- Increased ALT (43%)
- Anemia (42%)
- Diarrhea (37%)
- Hyponatremia (36%)
- Vomiting (33%)
- Hypoalbuminemia (29%)
- Hypokalemia (26%)
- Neutropenia (25%)
- Urticaria (25%)
- Capillary leak syndrome (22%)
- Hypocalcemia (20%)
- Increased AST (16%)
All grades (dinutuximab/IL-2)
- Pyrexia (65%)
- Paine (61%)
- Thrombocytopenia (61%)
- Lymphopenia (61%)
- Hyponatremia (55%)
- Infusion reactions (54%)
- Hypotension (54%)
- Increased ALT (48%)
- Anemia (42%)
- Hypokalemia (39%)
- Diarrhea (37%)
- Capillary leak syndrome (36%)
- Vomiting (35%)
- Neutropenia (32%)
- Urticaria (29%)
- Hypoalbuminemia (29%)
- Increased AST (21%)
- Hypocalcemia (21%)
Grade 3 or 4 (dinutuximab/RA)
- Pain (51%)
- Lymphopenia (51%)
- Pyrexia (40%)
- Thrombocytopenia (39%)
- Hypokalemia (37%)
- Anemia (34%)
- Neutropenia (34%)
- Infusion reactions (25%)
- Hyponatremia (23%)
- Capillary leak syndrome (23%)
- Hypotension (16%)
Grade 3 or 4 (dinutuximab/GM-CSF)
- Pain (43%)
- Lymphopenia (33%)
- Thrombocytopenia (31%)
- Anemia (21%)
- Neutropenia (19%)
- Increased ALT (15%)
- Hypokalemia (13%)
- Capillary leak syndrome (11%)
Grade 3 or 4 (dinutuximab/IL-2)
- Lymphopenia (50%)
- Pyrexia (37%)
- Pain (35%)
- Hypokalemia (33%)
- Thrombocytopenia (33%)
- Anemia (24%)
- Neutropenia (28%)
- Hyponatremia (21%)
- Capillary leak syndrome (20%)
- Infusion reactions (20%)
- Hypotension (16%)
- Increased ALT (13%)
- Diarrhea (13%)
1-10%
All grades (dinutuximab/RA)
- Increased weight (10%)
- Nausea (10%)
Grade 3 or 4 (dinutuximab/RA)
- Hemorrhage (6%)
- Hypertension (2%)
Grade 3 or 4 (dinutuximab/GM-CSF)
- Pyrexia (10%)
- Infusion reactions (10%)
- Urticaria (7%)
- Diarrhea (6%)
- Hypotension (5%)
- Hyponatremia (5%)
- Increased AST (4%)
- Hypoalbuminemia (3%)
- Vomiting (3%)
- Hypocalcemia (2%)
Grade 3 or 4 (dinutuximab/IL-2)
- Increased AST (7%)
- Urticaria (7%)
- Hypocalcemia (6%)
- Hypoalbuminemia (5%)
- Vomiting (2%)
Postmarketing Reports
Neurotoxicity: Prolonged urinary retention, transverse myelitis, and reversible posterior
leukoencephalopathy syndrome
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
Neurotoxicity
- 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
Urinary retention that persists for weeks to months following discontinuation of opioids reported; permanently discontinue therapy in patients with urinary retention that does not resolve following discontinuation of opioids
Transverse myelitis reported; promptly evaluate any patient with signs or symptoms of transverse myelitis such as weakness, paresthesia, sensory loss, or incontinence; permanently discontinue therapy in patients who develop transverse myelitis
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) reported; institute appropriate medical treatment and permanently discontinue therapy in patients with signs and symptoms of RPLS (e.g., severe headache, hypertension, visual changes, lethargy, or seizures)
Pregnancy & Lactation
Pregnancy
Based on mechanism of action, fetal harm may occur when administered to a pregnant female
There are no studies in pregnant females and no reproductive studies in animals to inform the drug-associated risk
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 2 months after final dose
Lactation
No information available on drug presence in human milk, effects on the breastfed infant, or effects on milk production
However, human IgG is present in human milk
Discontinue breastfeeding during treatment
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
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 Compatibilities
0.9% NaCl
IV Preparation
Inspect visually for particulate matter and discoloration prior to administration
Discard if solution is cloudy, has pronounced discoloration, or contains particulate matter
Aseptically withdraw the required volume from the single-use vial and inject into a 100 mL bag of 0.9% NaCl
Mix by gentle inversion; do NOT shake
Discard unused contents of the vial
IV Administration
Verify that patient has adequate hematologic, respiratory, hepatic, and renal function before initiating each dose
Not for administration as IV push or bolus
Initiate at an infusion rate of 0.875 mg/m2/hour for 30 min; gradually increase rate as tolerated to a maximum rate of 1.75 mg/m2/hr
Required pretreatment guidelines
-
IV hydration
- Infuse 0.9% NaCl 10 mL/kg IV over 1 hr just before each infusion
-
Analgesics
- Morphine sulfate (50 mcg/kg) IV immediately before infusion; continue as drip at infusion rate of 20-50 mcg/kg/hr during and for 2 hr following completion
- 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 IV morphine
-
Antihistamines and antipyretics
- Administer antihistamine (eg, diphenhydramine 0.5-1 mg/kg IV; not to exceed 50 mg IV over 10-15 min) starting 20 min before infusion and as tolerated q4-6hr during infusion
- Administer acetaminophen 10-15 mg/kg; not to exceed 650 mg 20 min before each infusion and q4-6hr PRN for fever or pain
- Administer ibuprofen 5-10 mg/kg q6hr PRN for control of persistent fever or pain
Storage
Vials
- Refrigerate at 2-8ºC (36-46ºF) in the outer carton to protect from light until time of use
- Do not freeze or shake the vial
Diluted infusion bag
- Refrigerate at 2-8ºC (36-46ºF) ; initiate infusion within 4 hr of preparation
- Discard bag 24 hr after preparation
Images
Formulary
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