Dinutuximab is a disialoganglioside (GD2)-directed monoclonal antibody that is indicated in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim), interleukin-2 (IL-2; aldesleukin), and 13-cis-retinoic acid (RA; isotretinoin) for the treatment of pediatric patients with high-risk neuroblastoma who achieved at least a partial response to prior first-line multiagent, multimodality therapy. Dinutuximab has black box warnings for infusion-related reactions and neurotoxicity.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Administer as an IV infusion; do NOT give as an IV bolus or push.
-Dilute prior to administration.
-Prior to each infusion, premedicate with analgesics, diphenhydramine, and acetaminophen and administer hydration with normal saline.
Dilution:
-Add the calculated dose/volume from the dinutuximab (3.5 mg/mL) vial to a 100 mL 0.9 sodium chloride injection, USP bag; mix gently and do not shake.
-Discard any unused portion of the dinutuximab vial.
-Storage following dilution: refrigerate the diluted solution (2 to 8 degrees C; 36 to 46 degrees F) and start the infusion within 4 hours of preparation; discard any unused diluted solution after 24 hours.
Intravenous Infusion:
-Administer the diluted solution IV over 10 to 20 hours.
-Start the infusion at a rate of 0.875 mg/m2/hour for 30 minutes, then increase as tolerated to a maximum rate of 1.75 mg/m2/hour.
-Monitor patients for symptoms of infusion-related reactions; infusion interruption, infusion rate reduction, or permanent infusion discontinuation may be necessary.
-Blood pressure support, bronchodilator therapy, and/or corticosteroids may need to be administered for severe reactions.
Hematologic toxicity including anemia (51% to 100%), lymphopenia (62%), neutropenia (39% to 99%), febrile neutropenia (4%), and thrombocytopenia (66% to 98%) has been reported in patients who received dinutuximab-containing therapy in clinical studies. Monitor complete blood counts at baseline and closely during therapy. Anemia (51% vs. 22%), lymphopenia (62% vs. 36%), neutropenia (39% vs. 16%), febrile neutropenia (4% vs. 0%), and thrombocytopenia (66% vs. 43%) occurred more often in pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Additionally, grade 3 or 4 anemia (34%), lymphopenia (51%), neutropenia (34%), and thrombocytopenia (39%) were reported in the dinutuximab-containing arm. In this trial, the incidence of hematologic adverse events reported in cycles of therapy that contained sargramostim (GM-CSF) or aldesleukin (IL-2) are as follows: anemia (GM-CSF: 42%; grade 3/4, 21%; IL-2: 42%; grade 3/4, 24%), lymphopenia (GM-CSF: 54%; grade 3/4, 33%; IL-2: 61%; grade 3/4, 33%) , neutropenia (GM-CSF: 25%; grade 3/4, 19%; IL-2: 32%; grade 3/4, 28%), and thrombocytopenia (GM-CSF: 62%; grade 3/4, 31%; IL-2: 61%; grade 3/4, 33%). In a single arm safety study (n = 104), anemia (100%; grade 3/4, 46%), neutropenia (99%; grade 3/4, 63%), and thrombocytopenia (98%; grade 3/4, 49%) were reported in patients who received dinutuximab in combination with isotretinoin, sargramostim, and aldesleukin.
Elevated hepatic enzymes (28% to 84%) and hypoalbuminemia (33% to 100%) have been reported in patients who received dinutuximab-containing therapy in clinical trials. Ensure patients have adequate hepatic function prior to starting each cycle of dinutuximab therapy; monitor liver function tests (LFTs) and assess patients for signs and symptoms of hepatic impairment. Increased AST level (28% vs. 7%), increased ALT level (56% vs. 31%), and hypoalbuminemia (33% vs. 3%) occurred more often in pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Additionally, grade 3 or 4 increased AST level (10%), increased ALT level (23%), and hypoalbuminemia (7%) were reported in the dinutuximab-containing arm. In this trial, the incidence of abnormal LFTs reported in cycles of therapy that contained sargramostim (GM-CSF) or aldesleukin (IL-2) are as follows: increased AST level (GM-CSF: 16%; grade 3/4, 4%; IL-2: 21%; grade 3/4, 7%), increased ALT level (GM-CSF: 43%; grade 3/4, 15%; IL-2: 48%; grade 3/4, 13%), and hypoalbuminemia (GM-CSF: 29%; grade 3/4, 3%; IL-2: 29%; grade 3/4, 5%). In a single arm safety study (n = 104), increased AST level (84%; grade 3/4, 929928%), increased ALT level (83%; grade 3/4, 13%), and hypoalbuminemia (100%; grade 3/4, 8%) were reported in patients who received dinutuximab in combination with isotretinoin, GM-CSF, and IL-2.
Proteinuria (16% to 66%) and increased serum creatinine level (15%) have been reported in patients who received dinutuximab-containing therapy in clinical trials. Ensure patients have adequate renal function prior to starting each cycle of dinutuximab therapy; monitor renal function (e.g., serum creatinine, creatinine clearance, glomerular filtration rate (GFR)) and assess patients for signs and symptoms of renal impairment. Proteinuria (16% vs. 3%) and increased serum creatinine level (15% vs. 6%) occurred more often in pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Additionally, grade 3 or 4 increased serum creatinine level (2%) was reported in the dinutuximab-containing arm. In a single arm safety study (n = 104), proteinuria/protein in urine (66%) and red blood cell casts in urine (38%) were reported in patients who received dinutuximab in combination with isotretinoin, sargramostim, and aldesleukin.
Hyperglycemia occurred in 18% of pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with 4% of patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Additionally, grade 3 or 4 hyperglycemia was reported in 6% of patients the dinutuximab-containing arm. In a single arm safety study (n = 104), hyperglycemia was reported in 87% of patients who received dinutuximab in combination with isotretinoin, sargramostim, and aldesleukin; grade 3 or 4 hyperglycemia occurred in 6% of patients.
Electrolyte abnormalities including hypocalcemia (27% to 97%), hypokalemia (43% to 82%), hypomagnesemia (12%), hyponatremia (58% to 93%), and hypophosphatemia (20% to 78%) have been reported in patients who received dinutuximab-containing therapy in clinical trials. Monitor serum electrolytes daily during therapy; permanently discontinue dinutuximab in patients who develop grade 4 hyponatremia despite appropriate fluid management. Hypocalcemia (27% vs. 0%), hypokalemia (43% vs. 4%), hypomagnesemia (12% vs. 1%), hyponatremia (58% vs. 12%), and hypophosphatemia (20% vs. 3%) occurred more often in pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Additionally, grade 3 or 4 hypocalcemia (7%), hypokalemia (37%), hypomagnesemia (2%), hyponatremia (23%), and hypophosphatemia (8%) were reported in the dinutuximab-containing arm. In this trial, the incidence of hematologic adverse events reported in cycles of therapy that contained sargramostim (GM-CSF) or aldesleukin (IL-2) are as follows: hypocalcemia (GM-CSF: 20%; grade 3/4, 2%; IL-2: 21%; grade 3/4, 6%), hypokalemia (GM-CSF: 26%; grade 3/4, 13%; IL-2: 39%; grade 3/4, 33%) and hyponatremia (GM-CSF: 36%; grade 3/4, 5%; IL-2: 55%; grade 3/4, 21%). In a single arm safety study (n = 104), hypocalcemia (97%; grade 3/4, 7%), hypokalemia (82%; grade 3/4, 41%), hyponatremia (93%; grade 3/4, 36%), and hypophosphatemia (78%; grade 3/4, 6%) were reported in patients who received dinutuximab in combination with isotretinoin, GM-CSF, and IL-2. Syndrome of inappropriate antidiuretic hormone (SIADH) secretion resulting in severe hyponatremia occurred in 2 adult patients with metastatic melanoma who received a related antiGD2 antibody in a small study (n = 12).
Gastrointestinal (GI) adverse events such as anorexia/decreased appetite (15% vs. 5%), diarrhea (43% vs. 15%), nausea (10% vs. 3%), and vomiting (46% vs. 19%) occurred more often in pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Additionally, grade 3 or 4 anorexia (10%), diarrhea (13%), nausea (2%), and vomiting (6%) were reported in the dinutuximab-containing arm. In this trial, the incidence of GI adverse events reported in cycles of therapy that contained sargramostim (GM-CSF) or aldesleukin (IL-2) are as follows: diarrhea (GM-CSF: 31%; grade 3/4, 6%; IL-2: 37%; grade 3/4, 13%) and vomiting (GM-CSF: 33%; grade 3/4, 3%; IL-2: 35%; grade 3/4, 2%).
Respiratory adverse events have been reported in patients who received dinutuximab-containing therapy in clinical trials. Ensure patients have adequate respiratory function prior to starting each cycle of dinutuximab therapy; monitor pulse oximetry and assess patients for signs and symptoms of impaired respiration. Hypoxia occurred in 24% of pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with 2% of patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Grade 3 or 4 hypoxia was reported in 12% of patients in the dinutuximab-containing arm. In a single arm safety study (n = 104), nasal congestion (20%) and wheezing (15%) were reported in patients who received dinutuximab in combination with isotretinoin, sargramostim, and aldesleukin.
Fever occurred in 72% of pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with 27% of patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Grade 3 or 4 fever was reported in 40% of patients in the dinutuximab-containing arm. In this trial, fever was reported less frequently in sargramostim-containing cycles (55%; grade 3/4, 10%) compared with aldesleukin-containing cycles (65%; grade 3/4, 37%).
Edema occurred in 17% of pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with 0% of patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial.
Weight gain occurred in 10% of pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with 0% of patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial.
Hypertriglyceridemia occurred in 16% of pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with 11% of patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Grade 3 or 4 hypertriglyceridemia was reported in 1% of patients in the dinutuximab-containing arm.
Bleeding occurred in 17% of pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with 6% of patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Grade 3 or 4 bleeding was reported in 6% of patients in the dinutuximab-containing arm. The bleeding term in this study included GI bleeding, upper GI bleeding, hematochezia/rectal bleeding, hematemesis, hematuria, urinary tract bleeding, renal bleeding, epistaxis, respiratory tract bleeding, disseminated intravascular coagulation (DIC), catheter-site bleeding, and hematoma.
Hypertension (14% vs. 7%) and sinus tachycardia (19% vs. 1%) occurred more often in pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Additionally, grade 3 or 4 hypertension (2%), and tachycardia (2%) were reported in the dinutuximab-containing arm.
Hypotension has been reported in 60% of patients who received dinutuximab-containing therapy in a randomized, phase III study. Administer hydration prior to each infusion. Monitor blood pressure closely during therapy. Therapy interruption, infusion rate reduction, and supportive care may be necessary in patients who develop symptomatic hypotension, systolic blood pressure (SBP) less than the lower limit of normal for age, or SBP decreased > 15% from baseline. Hypotension occurred in 60% of pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with 3% of patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Grade 3 or 4 hypotension was reported in 16% of patients in the dinutuximab-containing arm. In this trial, hypotension was reported less frequently in sargramostim-containing cycles (43%; grade 3/4, 5%) compared with aldesleukin-containing cycles (54%; grade 3/4, 16%).
Serious infection including bacteremia and sepsis has been reported in patients who received dinutuximab-containing therapy in a randomized, phase III study. Monitor patients closely for signs and symptoms of systemic infection. If a patient develops a serious infection, discontinue therapy until the infection resolves. Therapy may be restarted in subsequent treatment cycles. Sepsis (18% vs. 9%; grade 3 or 4, 16% vs. 9%) and grade 3 or 4 bacteremia (13% vs. 5%) and device-related infection (16% vs. 11%) occurred more often in pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial.
Antibody formation to dinutuximab was reported in 20.6% of patients (n = 86 of 418) who received dinutuximab, sargramostim, and aldesleukin in pooled results from 3 clinical studies. Of the 86 patients who had anti-dinutuximab antibodies (ADA), 52.3% developed neutralizing antibodies. ADA occurred in 48.1% of patients (n = 13 of 27) who received dinutuximab, lenalidomide, and isotretinoin in another clinical trial; 15.4% of these patients (n = 2 of 13) developed neutralizing antibodies. There was no clinically significant difference in the incidence or severity of adverse events in patients with ADA compared with patients without ADA. It is not known if ADA affects the efficacy of dinutuximab.
Neurotoxicity may occur with dinutuximab therapy. Pain (85%) and peripheral neuropathy (13%) have been reported in patients who received dinutuximab-containing therapy in clinical studies. Pain occurred most often during the dinutuximab infusion and included abdominal pain, upper abdominal pain, arthralgia, back pain, bladder pain, bone pain, chest pain (unspecified), extremity pain, facial pain, gingival pain, infusion-related pain, musculoskeletal pain in the chest, myalgia, neck pain, neuralgia/neuropathic pain, oropharyngeal pain, and proctalgia. Give an IV opioid prior to, during, and for 2 hours following the completion of the dinutuximab infusion. Reduce the infusion rate for grade 3 pain. Permanently discontinue therapy in patients who develop severe pain that does not respond to reduction in infusion rate and maximum supportive care measures, grade 3 sensory neuropathy that interferes with daily activities (for > 2 weeks) or grade 4 sensory neuropathy, or grade 2 peripheral motor neuropathy. Pain (85% vs. 16%) and peripheral neuropathy (13% vs. 6%) occurred more often in pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Additionally, grade 3 or 4 pain (51%) and peripheral neuropathy (3%) were reported in patients in the dinutuximab-containing arm; peripheral sensory neuropathy occurred in 2 patients (1%) and severe peripheral motor neuropathy occurred in 2 patients (1%). In this trial, pain was reported more frequently in sargramostim-containing cycles (77%; grade 3/4, 43%) compared with aldesleukin-containing cycles (61%; grade 3/4, 35%). In a single arm safety study (n = 104), peripheral sensory neuropathy was reported in 9% of patients who received dinutuximab in combination with isotretinoin, sargramostim, and aldesleukin; the median duration of peripheral sensory neuropathy was 9 days (range, 3 to 163 days). No patients experienced peripheral motor neuropathy in this study. Severe motor neuropathy occurred in 2 adult patients with metastatic melanoma (off-label use) who received a related anti-GD2 antibody in a small study (n = 12). One patient had lower extremity weakness and was unable to ambulate for approximately 6 weeks. A second patient developed severe lower extremity weakness and was unable to ambulate without assistance for about 16 weeks and had a neurogenic bladder for about 3 weeks; a complete resolution of motor neuropathy was not documented in this patient.
Neurologic eye disorders including blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema have been reported in patients who received dinutuximab-containing therapy in clinical studies. Stop the infusion and reduce the dose in patients who experience a visual disturbance (e.g., dilated pupil with sluggish light reflex) during therapy. Permanently discontinue therapy if a patient has a recurrence of the visual disturbance or has partial or total vision loss. Blurred vision (2% vs. 0%), diplopia (< 1% vs. 0%), mydriasis (< 1% vs. 0%), and unequal pupillary size (< 1% vs. 0%) occurred more often in pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. In a single arm safety study (n = 104), eye disorders occurred in 15% of patients who received dinutuximab in combination with isotretinoin, sargramostim, and aldesleukin; the median duration of eye disorders was 4 days (range, 0 to 221 days) in the patients who recovered vision. A complete resolution of the eye disorder was not documented in 3 patients (3%).
An atypical hemolytic-uremic syndrome (HUS) has been reported rarely in patients who received dinutuximab-containing therapy in clinical studies. Permanently discontinue dinutuximab and start supportive therapy if a patient develops HUS. In a single-arm, expanded access study (n = 783), HUS was reported in 2 patients following the first cycle of dinutuximab therapy given in combination with isotretinoin, sargramostim, and aldesleukin. HUS resulted in renal insufficiency, electrolyte abnormalities, anemia, and hypertension; no evidence of infection was noted. One patient experienced the atypical HUS again upon rechallenge with dinutuximab.
Capillary leak syndrome was reported in 40% of patients who received dinutuximab-containing therapy in a randomized, phase III study; 1 case was fatal. Therapy interruption, infusion rate reduction, or permanent discontinuation may be necessary in patients who develop capillary leak syndrome. Capillary leak syndrome occurred in 40% of pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with 1% of patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Additionally, grade 3 or 4 capillary leak syndrome was reported in 23% of patients in the dinutuximab-containing arm. In this trial, capillary leak syndrome was reported less frequently in sargramostim-containing cycles (22%; grade 3/4, 11%) compared with aldesleukin-containing cycles (36%; grade 3/4, 20%).
Serious and potentially life-threatening infusion-related reactions including facial edema (angioedema) and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension have been reported in 60% of patients who received dinutuximab-containing therapy in a randomized, phase III study. Reactions generally occurred during the infusion or within 24 hours after the infusion ended. Premedicate patients with diphenhydramine and acetaminophen and give hydration prior to each infusion. Monitor patients closely for signs and symptoms of a reaction during the infusion and for at least 4 hours following the completion of each infusion. Access to cardiopulmonary resuscitation medication and equipment is necessary. Therapy interruption, infusion rate reduction, or permanent discontinuation may be necessary in patients who develop infusion-related reactions. Permanently discontinue dinutuximab if anaphylactoid reactions (anaphylaxis) occur. Infusion-related reactions (60% vs. 9%) and urticaria (37% vs. 3%) occurred more often in pediatric patients with high-risk neuroblastoma who received dinutuximab and isotretinoin plus sargramostim (cycles 1, 3, and 5) and aldesleukin (cycles 2 and 4) therapy (n = 134) compared with patients who received 6 cycles of isotretinoin alone (n = 106) in a randomized, phase III trial. Additionally, grade 3 or 4 infusion-related reactions (25%) including urticaria (13%) and anaphylaxis (1%) were reported in patients in the dinutuximab-containing arm. In this trial, the incidence of select adverse events in cycles containing sargramostim (GM-CSF) or aldesleukin (IL-2) was as follows: infusion-related reactions (GM-CSF: 47%; grade 3/4, 10%; IL-2: 54%; grade 3/4, 20%) and urticaria (GM-CSF: 25%; grade 3/4, 7%; IL-2: 29%; grade 3/4, 7%). In a single-arm, expanded access study (n = 783), 1 patient (0.1%) died following multiple episodes of cardiac arrest within 24 hours of receiving dinutuximab in combination with isotretinoin, GM-CSF, and IL-2.
Urinary retention that persisted for weeks to months following discontinuation of opioids has been reported in postmarketing surveillance of dinutuximab. Permanently discontinue dinutuximab in patients with urinary retention that does not resolve after opioid agents are discontinued.
Transverse myelitis has been reported in postmarketing surveillance of dinutuximab. Promptly evaluate any patient with signs or symptoms of transverse myelitis (e.g., weakness, paresthesias, sensory loss, or urinary incontinence); permanently discontinue dinutuximab in patients who develop transverse myelitis.
Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in postmarketing surveillance of dinutuximab. In patients with signs and symptoms of RPLS (e.g., severe headache, hypertension, visual changes, lethargy, or seizures), permanently discontinue dinutuximab and start appropriate medical treatment.
Serious and potentially life-threatening infusion-related reactions including anaphylaxis have been reported in patients who received dinutuximab. Reactions generally occurred during or within 24 hours after infusion ended. Use is contraindicated in patients who have had an anaphylactic reaction to dinutuximab. Premedicate patients with diphenhydramine and acetaminophen and give hydration prior to each infusion. Monitor patients closely for signs and symptoms of a reaction during the infusion and for at least 4 hours following the completion of each infusion. Access to cardiopulmonary resuscitation medication and equipment is necessary. Therapy interruption, infusion rate reduction, or permanent discontinuation may be necessary in patients who develop infusion-related reactions.
Neurotoxicity (e.g., severe neuropathic pain and sensory and motor peripheral neuropathy) has been reported in patients who received dinutuximab. Give an IV opioid prior to, during, and for 2 hours following the completion of the dinutuximab infusion. Reduce the infusion rate if grade 3 pain occurs. Permanently discontinue therapy in patients who develop severe pain that does not respond to reduction in infusion rate and maximum supportive care measures, grade 3 sensory neuropathy that interferes with daily activities (for > 2 weeks) or grade 4 sensory neuropathy, or grade 2 peripheral motor neuropathy.
Severe hypotension has been reported in patients who received dinutuximab. Administer hydration prior to each infusion. Monitor blood pressure closely during therapy. Therapy interruption, infusion rate reduction, and supportive care measures may be necessary in patients who develop symptomatic hypotension, systolic blood pressure (SBP) less than the lower limit of normal for age, or SBP decreased > 15% from baseline.
Serious infections including bacteremia and sepsis have been reported in patients who received dinutuximab. Monitor patients closely for signs and symptoms of systemic infection. If a patient develops a serious infection, discontinue therapy until the infection resolves. Therapy may be restarted in subsequent treatment cycles.
Neurological ocular disease (e.g., blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema) has been reported rarely in patients who received dinutuximab. Stop the infusion and reduce the dose in patients who experience a visual disturbance (e.g., dilated pupil with sluggish light reflex) during therapy. Permanently discontinue therapy if a patient has a recurrence of the visual disturbance or has partial or total vision loss.
Severe hematologic toxicity including thrombocytopenia, anemia, neutropenia, and febrile neutropenia has been reported in patients who received dinutuximab. Obtain complete blood counts at baseline and monitor blood counts closely during therapy.
Severe electrolyte imbalance/abnormalities (e.g., hyponatremia, hypokalemia, and hypocalcemia) have been reported in patients who received dinutuximab. Syndrome of inappropriate antidiuretic hormone secretion resulting in severe hyponatremia occurred in 2 adult patients with metastatic melanoma (off-label use) who received a related anti-GD2 antibody in a small study (n = 12). Monitor serum electrolytes daily during therapy; permanently discontinue dinutuximab in patients who develop grade 4 hyponatremia despite appropriate fluid management.
An atypical hemolytic-uremic syndrome (HUS) has been reported rarely in patients who received dinutuximab. Permanently discontinue dinutuximab and start supportive therapy if a patient develops HUS.
Capillary leak syndrome has been reported in patients who received dinutuximab; some cases were fatal. Therapy interruption, infusion rate reduction, or permanent discontinuation may be necessary in patients who develop capillary leak syndrome.
Hypoxia has been reported with dinutuximab in clinical trials. Ensure patients have adequate respiratory function prior to starting each cycle of dinutuximab therapy; monitor pulse oximetry and assess patients for signs and symptoms of impaired respiration. Pediatric patients with neuroblastoma who also had respiratory insufficiency (i.e., dyspnea at rest and peripheral arterial oxygen saturation of < 94% on room air) were ineligible for study treatment with dinutuximab in a randomized, phase III trial.
Dinutuximab has not been evaluated in patients with baseline hepatic impairment. Elevated hepatic enzyme levels have been reported with dinutuximab in clinical trials. Ensure patients have adequate hepatic function prior to starting each cycle of dinutuximab therapy; monitor liver function tests and assess patients for signs and symptoms of hepatic impairment. Pediatric patients with neuroblastoma who also had hepatic disease (i.e., total bilirubin level >= 1.5 times the upper limit of normal (ULN) and ALT level >= 5 times the ULN) were ineligible for study treatment with dinutuximab in a randomized, phase III trial.
Dinutuximab has not been evaluated in patients with baseline renal impairment. Proteinuria and increased serum creatinine (SCr) levels have been reported with dinutuximab in clinical trials. Ensure patients have adequate renal function prior to starting each cycle of dinutuximab therapy; monitor renal function (e.g., SCr, creatinine clearance, glomerular filtration rate (GFR)) and assess patients for signs and symptoms of renal impairment. Pediatric patients with neuroblastoma who also had renal disease (i.e., GFR < 70 mL/min/1.73 m2) were ineligible for study treatment with dinutuximab in a randomized, phase III trial.
Urinary retention that persisted for weeks to months following the discontinuation of opioid drugs has been reported with dinutuximab use. Permanently discontinue dinutuximab in patients with urinary retention that does not resolve after opioid drugs are discontinued.
Dinutuximab may cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Although there have been no studies in humans or animals evaluating the use of dinutuximab during pregnancy; some monoclonal antibodies are transported across the placenta. The transfer of these antibodies increases as pregnancy progresses resulting in the largest amount transferred during the third trimester. Discuss the potential hazard to the fetus if dinutuximab is used during pregnancy or if a patient becomes pregnant while taking this drug.
It is not known whether dinutuximab is secreted in human milk or if it affects the breast fed infant or milk production. It is known that human IgG is present in human milk. Because of the potential of serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding during treatment with dinutuximab.
Counsel patients about the reproductive risk and contraception requirements during dinutuximab treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 2 months after treatment with dinutuximab. Patients who become pregnant while receiving dinutuximab should be apprised of the potential hazard to the fetus.
For the treatment of high-risk neuroblastoma in patients who achieve at least a partial response to first-line multiagent, multimodality therapy in combination with 13-cis-retinoic acid (isotretinoin), granulocyte-macrophage colony-stimulating factor (sargramostim), and interleukin-2 (aldesleukin):
NOTE: Dinutuximab has been designated an orphan drug by the FDA for this indication.
Intravenous dosage:
Children and Adolescents: 17.5 mg/m2/dose as an IV infusion over 10 to 20 hours on scheduled days for 5 cycles in combination with isotretinoin, sargramostim, and aldesleukin. On cycles 1, 3, and 5: give sargramostim 250 mcg/m2/day subcutaneously (or as an IV infusion over 2 hours) on days 1 to 14; dinutuximab on days 4, 5, 6, and 7; and isotretinoin 160 mg/m2/day PO in 2 divided doses rounded to the nearest 10 mg in patients weighing more than 12 kg (or 5.33 mg/kg/day PO in 2 divided doses rounded to the nearest 10 mg in patients weighing 12 kg or less) on days 11 to 24. On cycles 2 and 4: give aldesleukin 3 million international units/m2/day as a continuous IV infusion over 24 hours on days 1, 2, 3, and 4 and aldesleukin 4.5 million international units/m2/day as a continuous IV infusion over 24 hours on days 8, 9, 10, and 11; dinutuximab on days 8, 9, 10, and 11; and isotretinoin 160 mg/m2/day PO in 2 divided doses rounded to the nearest 10 mg in patients weighing more than 12 kg (or 5.33 mg/kg/day PO in 2 divided doses rounded to the nearest 10 mg in patients weighing 12 kg or less) on days 15 to 28; give no therapy on days 29 to 32. Begin cycles 2 and 4 on day 25 and cycles 3 and 5 on day 33. Continue isotretinoin (same daily dose) for 14 days for 1 additional cycle (total of 6 cycles). Therapy interruption, infusion rate or dose reduction, or permanent discontinuation may be necessary in patients who develop severe adverse reactions. Infusion rate: initiate at 0.875 mg/m2/hour for 30 minutes, then gradually increase the rate as tolerated to a maximum rate of 1.75 mg/m2/hour. Pretreatment (prior to each dinutuximab infusion): hydration with 0.9% Sodium Chloride Injection 10 mL/kg IV over 1 hour given before the infusion, analgesics (e.g., morphine sulfate 50 mcg/kg IV immediately prior to starting the infusion), diphenhydramine (0.5 to 1 mg/kg up to a maximum dose of 50 mg IV over 10 to 15 minutes given 20 minutes prior to the infusion), and acetaminophen (10 to 15 mg/kg up to a maximum dose of 650 mg given 20 minutes prior to the infusion). Additional side effect management treatment: morphine sulfate continuous IV infusion (20 to 50 mcg/kg/hour) during and for 2 hours following the end of the infusion (fentanyl or hydromorphone may be substituted for analgesia if morphine sulfate is not tolerated), morphine sulfate 25 to 50 mcg/kg/dose IV every 2 hours as needed for pain followed by an increase in the morphine sulfate infusion rate in clinically stable patients (consider adding gabapentin or lidocaine in conjunction with IV morphine if pain is inadequately managed with opioids), diphenhydramine 0.5 to 1 mg/kg up to a maximum dose of 50 mg IV every 4 to 6 hours as tolerated, acetaminophen 10 to 15 mg/kg up to a maximum dose of 650 mg every 4 to 6 hours as needed for fever or pain, and ibuprofen 5 to 10 mg/kg every 6 hours as needed for control of persistent fever or pain. Literature: At a median follow-up 2.1 years (range, 4 days to 6.9 years), treatment with dinutuximab, isotretinoin, sargramostim, and aldesleukin resulted in a significantly improved 2-year event-free survival rate (primary endpoint) compared with isotretinoin alone (66% vs. 46%; p = 0.01) in pediatric patients (median age, 3.8 years; range, 0.94 to 15.3 years) with high-risk neuroblastoma who had completed induction therapy, an autologous stem-cell transplantation, and radiotherapy in a multicenter, randomized, phase III trial (n = 226; the ANBL0032 trial). The 2-year overall survival rate was also significantly improved in patients treated in the dinutuximab arm (86% vs. 75%; p = 0.02).
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicities:
Infusion-Related Reactions
Mild to moderate reaction (e.g., rash, fever, rigors, localized urticaria): reduce the infusion rate to 50% of the previous rate; may gradually increase the infusion rate to a maximum of 1.75 mg/m2/hour following symptom resolution.
Prolonged or severe reaction (e.g., mild bronchospasm with no other symptoms or angioedema not affecting the airway): stop the infusion; if symptoms resolve rapidly, reduce the infusion rate to 50% of the previous rate. For a first recurrence, stop the infusion and resume the next day; if symptoms resolve and treatment is continued, premedicate with hydrocortisone 1 mg/kg (maximum dose, 50 mg) IV and give dinutuximab at an infusion rate of 0.875 mg/m2/hour in an intensive care setting. For a second recurrence, permanently discontinue dinutuximab.
Life-threatening reaction (e.g., grade 3 or 4 anaphylaxis): permanently discontinue dinutuximab.
Neuropathy
Grade 2 or greater peripheral motor neuropathy: permanently discontinue dinutuximab.
Grade 3 sensory neuropathy that interferes with daily activities (for greater than 2 weeks) or grade 4 sensory neuropathy: permanently discontinue dinutuximab.
Pain
Grade 3 pain: reduce the infusion rate to 0.875 mg/m2/hour.
Grade 3 pain not responsive to maximum supportive measures and decreased infusion rate: permanently discontinue dinutuximab.
Capillary Leak Syndrome
Moderate to severe toxicity: stop the infusion; reduce the infusion rate to 50% of the previous rate following symptom resolution.
Life-threatening toxicity: stop the infusion and discontinue therapy until the treatment next cycle. In subsequent cycles, reduce the infusion rate to 50% of the previous rate. For a first recurrence, permanently discontinue dinutuximab.
Hypotension
Severe hypotension (e.g., symptomatic hypotension, systolic blood pressure (SBP) less than the lower limit of normal for age, or SBP decreased greater than 15% from baseline): stop the infusion; reduce the infusion rate to 50% of the previous rate following symptom resolution. If blood pressure is stable for 2 hours at the reduced infusion rate, gradually increase the infusion rate to a maximum of 1.75 mg/m2/hour.
Infection
Severe infection or sepsis: discontinue therapy until the infection resolves; may continue with subsequent treatment cycles.
Neurologic Disorders of the Eye
Visual disturbances (e.g., dilated pupil with sluggish light reflex) not including visual loss: stop the infusion; reduce the dose by 50% (from 17.5 mg/m2/dose to 8.75 mg/m2/dose) following symptom resolution. For a first recurrence, permanently discontinue dinutuximab.
Subtotal or total vision loss: permanently discontinue dinutuximab.
Other Toxicities
Grade 3 or 4 serum sickness: permanently discontinue dinutuximab.
Grade 4 hyponatremia despite appropriate fluid management: permanently discontinue dinutuximab.
Hemolytic uremic syndrome: permanently discontinue dinutuximab.
Urinary retention that persists following discontinuation of opioids: permanently discontinue dinutuximab.
Transverse myelitis: permanently discontinue dinutuximab.
Reversible posterior leukoencephalopathy syndrome (RPLS): permanently discontinue dinutuximab.
Maximum Dosage Limits:
-Adolescents
17.5 mg/m2/dose IV on scheduled days for 4 consecutive days/cycle.
-Children
17.5 mg/m2/dose IV on scheduled days for 4 consecutive days/cycle.
Patients with Hepatic Impairment Dosing
Dinutuximab has not been evaluated in patients with hepatic impairment. Specific guidelines for dosage adjustments in hepatic impairment are not available.
Patients with Renal Impairment Dosing
Dinutuximab has not been evaluated in patients with renal impairment. Specific guidelines for dosage adjustments in renal impairment are not available.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Dinutuximab is a chimeric monoclonal antibody (also known as ch 14.18), composed of a combination of mouse and human DNA, that works by binding to glycolipid disialoganglioside (GD2) on the cell surface of neuroblastoma cells and cells of neuroectodermal origin, including the central nervous system and peripheral nerves. This binding results in cell lysis through antibody-dependent cell-mediated and complement-dependent cytotoxicity. Neuroblastomas have a high expression of GD2 and GD2 expression is limited in normal tissues. The addition of sargramostim (GM-CSF) enhances the dinutuximab-mediated lysis of neuroblastoma cells by granulocytes.
Dinutuximab is administered as an IV infusion. In a population pharmacokinetic (PK) analysis of dinutuximab in 27 children with high-risk neuroblastoma (mean age, 3.9 +/- 1.9 years), the mean steady state volume of distribution (Vd) was 5.4 liters (coefficient of variation (CV), 28%), the clearance was 0.21 L/day (CV, 62%), and the terminal half-life was 10 days (CV, 56%) following treatment with dinutuximab (17.5 mg/m2/day as an IV infusion over 10 to 20 hours for 4 consecutive days, repeated every 28 days), isotretinoin, and sargramostim (GM-CSF). The PK parameters of dinutuximab were evaluated in 14 pediatric patients with high-risk neuroblastoma (median age, 4.3 years; range, 1.2 to 7.3 years) who received dinutuximab (25 mg/m2/day as an IV infusion given over 10 hours for 4 consecutive days, repeated every 28 days) with isotretinoin and GM-CSF on cycles 1, 3, or 5 of the Children's Oncology Group protocol ANBL0032. In this study, the mean steady state Vd was 0.45 L/kg (CV, 45%), the mean clearance was 1.9 L/day X m2 (CV, 32%), and the mean half-life was 6.9 days (CV, 47%). Using the current recommended dinutuximab dose of 17.5 mg/m2/day for 4 consecutive days, the steady state Vd and clearance values are expected to be 32% lower than the values presented in this PK study.
-Route-Specific Pharmacokinetics
Intravenous Route
In a population pharmacokinetic (PK) analysis of dinutuximab in 27 children with high-risk neuroblastoma (mean age, 3.9 +/- 1.9 years), the Cmax was 11.5 mcg/mL (coefficient of variation (CV), 20%) following treatment with dinutuximab (17.5 mg/m2/day as an IV infusion over 10 to 20 hours for 4 consecutive days, repeated every 28 days), isotretinoin, and sargramostim (GM-CSF). The PK parameters of dinutuximab were evaluated in 14 pediatric patients with high-risk neuroblastoma (median age, 4.3 years; range, 1.2 to 7.3 years) who received dinutuximab (25 mg/m2/day as an IV infusion given over 10 hours for 4 consecutive days, repeated every 28 days) with isotretinoin and GM-CSF on cycles 1, 3, or 5 of the Children's Oncology Group protocol ANBL0032. In this study, the mean Cmax was 11 mcg/mL (coefficient of variation (CV), 29%) and the mean AUC (from time 0 to 28 days) was 1320 mcg X hours/mL. Of note, the current recommended dinutuximab dose is 17.5 mg/m2/day for 4 consecutive days.
-Special Populations
Other
Antibody Formation
Dinutuximab clearance was 60% higher in patients who tested positive for anti-dinutuximab antibodies (ADA) compared with patients who tested negative for ADA in clinical trials.