Dinutuximab, a chimeric human-murine anti-glycolipid disialoganglioside (anti-GD2) monoclonal antibody, is an antineoplastic agent.1, 2, 6, 7, 11
Dinutuximab is used in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin for the treatment of high-risk neuroblastoma in pediatric patients who previously achieved at least a partial response to first-line antineoplastic therapy and multimodality therapy.1, 2 The drug has been designated an orphan drug by FDA for use in this condition.3
The current indication for dinutuximab is based principally on the results of a randomized, open-label, multicenter study in 226 pediatric patients with high-risk neuroblastoma.1, 2 The primary measure of efficacy was event-free survival as assessed by the investigator.1, 2 All patients had received prior therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplantation, and radiation therapy to residual soft tissue disease.1 Patients were enrolled if they achieved at least a partial response prior to undergoing autologous stem cell transplantation and if there was no evidence of disease progression following completion of first-line multimodality therapy.1, 2 Patients enrolled in the study also were required to have adequate pulmonary (no dyspnea at rest and peripheral arterial oxygen saturation of at least 94% on room air), cardiac (shortening fraction of more than 30% by echocardiogram [ECHO] or ejection fraction of 55% by gated radionuclide study), hematologic (platelet count of 20,000/mm3 or more and total absolute phagocyte count [APC] of 1000/mm3 or more),13 hepatic (total bilirubin concentrations less than 1.5 times the upper limit of normal [ULN] and ALT concentrations less than 5 times the ULN), and renal (glomerular filtration rate [GFR] of at least 70 mL/minute per 1.73 m2) function.1, 2 The median age of patients was 3.8 years (range: 0.9 months to 15 years1, 10 ), 82% of patients were white, and 80% had stage 4 disease according to the International Neuroblastoma Staging System (INSS); 35, 43, and 23% of these patients achieved a complete response, a very good partial response, and a partial response, respectively, to therapy they received prior to undergoing autologous stem cell transplantation.1
In this study, patients were randomized in a 1:1 ratio between days 50-77 following autologous stem cell transplantation to receive either dinutuximab in combination with isotretinoin and alternating cycles of sargramostim (GM-CSF) and aldesleukin (IL-2) or isotretinoin alone.1, 2 Patients in the control group received isotretinoin 160 mg/m2 (for patients weighing more than 12 kg) or 5.33 mg/kg (for patients weighing 12 kg or less) daily administered orally in 2 divided doses for 14 consecutive days for six 28-day cycles.1, 2 Patients in the dinutuximab group received the same dosage of isotretinoin administered on days 11-24 of a 24-day cycle during cycles 1, 3, and 5 and on days 15-28 of a 32-day cycle during cycles 2 and 4 with the addition of dinutuximab (dosage equivalent to 17.5 mg/m2 of the commercially available preparation [i.e., 25 mg/m2 of drug product lots used during the clinical trial] administered by IV infusion1, 10 ) on days 4-7 and sargramostim (250 mcg/m2 administered by subcutaneous injection or IV infusion over 2 hours) on days 1-14 during cycles 1, 3, and 5; during cycles 2 and 4, dinutuximab was administered on days 8-11 and aldesleukin was administered by continuous IV infusion on days 1-4 (dosage of 3 million units/m2 daily) and days 8-11 (dosage of 4.5 million units/m2 daily).1, 2 During cycle 6, patients received isotretinoin alone at the same dosage as in cycles 1-5.1, 2 Patients with systemic infections and those requiring concomitant systemic corticosteroids or immunosuppressive agents were excluded from the study.1 (See Drug Interactions: Immunosuppressive Therapy.)
Although median event-free survival for patients receiving the combination regimen had not been reached at the time of the primary analysis, median event-free survival appeared to be prolonged in patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with those receiving isotretinoin alone.1, 10 At the time of the primary analysis, median overall survival had not been reached in either group; however, overall survival also appeared to be prolonged in patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with those receiving isotretinoin alone.1
Adequate pulmonary, hematologic, hepatic, and renal function should be confirmed before administration of the first dinutuximab dose of each treatment cycle.1 (See Uses: Neuroblastoma.)
To minimize the risk of infusion-related adverse events associated with dinutuximab, a premedication regimen consisting of an antihistamine and acetaminophen should be administered prior to each dinutuximab infusion.1, 5 An antihistamine (e.g., IV diphenhydramine hydrochloride 0.5-1 mg/kg [up to a maximum dose of 50 mg] over 10-15 minutes) should be administered beginning 20 minutes prior to each infusion of dinutuximab and every 4-6 hours as tolerated during the infusion.1, 5 Acetaminophen 10-15 mg/kg (up to a maximum dose of 650 mg) should be administered orally 20 minutes prior to each infusion of dinutuximab and then every 4-6 hours as needed for fever or pain.1, 10 If persistent fever or pain occurs, ibuprofen 5-10 mg/kg may be administered every 6 hours as needed.1 (See Infusion-related Effects under Warnings/Precautions: Warnings, in Cautions.)
To reduce pain associated with dinutuximab, the manufacturer recommends IV administration of morphine sulfate 50 mcg/kg immediately before each dinutuximab infusion.1, 5 Morphine sulfate should be continued at an infusion rate of 20-50 mcg/kg per hour during and for 2 hours following completion of the dinutuximab infusion.1 Additional doses of IV morphine sulfate 25-50 mcg/kg may be administered as needed for pain every 2 hours followed by an increase in the morphine sulfate infusion rate in clinically stable patients.1 Fentanyl citrate or hydromorphone hydrochloride may be considered if morphine sulfate is not tolerated.1 If pain persists despite use of opiate analgesics, the manufacturer recommends that use of gabapentin or lidocaine in conjunction with IV morphine sulfate be considered.1 (See Pain under Warnings/Precautions: Warnings, in Cautions.)
Because of the potential for hypotension, adequate IV fluids should be administered prior to each infusion of dinutuximab.1 The manufacturer recommends IV hydration with 0.9% sodium chloride injection 10 mL/kg over 1 hour immediately before each dinutuximab infusion.1
Clinicians should consult the respective manufacturers' labelings or published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens.
Restricted Distribution Program
Dinutuximab can only be obtained through a specialty pharmacy.9 Clinicians may consult the Unituxin® website for specific availability information ([Web]).9
Dinutuximab is administered by IV infusion over 10-20 hours.1 The drug should not be administered by rapid IV injection, such as IV push or bolus. 1
Dinutuximab should be infused at an initial rate of 0.875 mg/m2 per hour for 30 minutes.1 The rate of infusion may be gradually increased as tolerated to a maximum infusion rate of 1.75 mg/m2 per hour.1
Dinutuximab injection concentrate must be diluted prior to administration.1 Prior to dilution, the injection concentrate should be inspected visually for particulate matter and discoloration.1 The solution should be clear to slightly opalescent and colorless; the solution should not be used if it is cloudy or discolored or if particulate matter is present.1 The appropriate dose (17.5 mg/m2 per treatment day) of dinutuximab injection concentrate (containing 3.5 mg/mL) should be withdrawn and added to an infusion bag containing 100 mL of 0.9% sodium chloride injection.1 This diluted solution should be mixed by gentle inversion and should not be shaken.1
Diluted solutions of the drug should be stored under refrigeration (2-8°C).1 Infusion of the drug should be initiated within 4 hours of dilution, and the drug should be discarded 24 hours after dilution.1
Any unused portion left in the vial should be discarded since dinutuximab injection concentrate contains no preservative.1
For the treatment of high-risk neuroblastoma in pediatric patients who previously achieved at least a partial response to first-line therapy, the recommended dosage of dinutuximab is 17.5 mg/m2 daily by IV infusion over 10-20 hours on days 4-7 of a 24-day cycle during cycles 1, 3, and 5; granulocyte-macrophage colony-stimulating factor (GM-CSF) and isotretinoin also are administered during these cycles.1 For cycles 2 and 4, the same dosage of dinutuximab is administered on days 8-11 of a 32-day cycle; interleukin-2 (IL-2) and isotretinoin also are administered during these cycles.1 In the principal efficacy study, dinutuximab therapy was continued for a maximum of 5 cycles. During cycle 6, isotretinoin is administered alone.1 (See Uses: Neuroblastoma.)
Dosage Modification for Toxicity
If toxicity occurs, temporary or permanent discontinuance of dinutuximab may be required based on causality.1
Dinutuximab should be permanently discontinued in patients experiencing grade 3 or 4 anaphylaxis, grade 3 or 4 serum sickness, grade 3 pain unresponsive to optimal pain management, grade 4 peripheral sensory neuropathy, grade 3 peripheral sensory neuropathy that interferes with daily activities for more than 2 weeks, grade 2 peripheral motor neuropathy, subtotal or total loss of vision, grade 4 hyponatremia despite appropriate fluid management, or hemolytic uremic syndrome.1 (See Cautions: Warnings/Precautions.)
If mild or moderate infusion-related reactions (e.g., transient rash, fever, rigors, localized urticaria) occur, appropriate symptomatic therapy should be provided and the rate of infusion should be reduced by 50%.1 If the patient responds promptly to symptomatic therapy, the infusion rate may be gradually increased following resolution of the reaction up to a maximum infusion rate of 1.75 mg/m2 per hour.1 (See Infusion-related Effects under Warnings/Precautions: Warnings, in Cautions.)
If prolonged or severe infusion-related reactions (e.g., mild bronchospasm without other symptoms, angioedema that does not affect the airway) occur, the dinutuximab infusion should be interrupted immediately; if the reaction resolves rapidly, the infusion may be resumed but the rate of infusion should be reduced by 50%.1
Following a second episode of prolonged or severe infusion-related reactions, the dinutuximab infusion should be interrupted until the next day.1 If continued therapy is warranted and the reaction has resolved, premedication with IV hydrocortisone 1 mg/kg (up to a maximum dose of 50 mg) should be administered and dinutuximab should be administered at a rate of 0.875 mg/m2 per hour in an intensive care unit (ICU).1
Following a third episode of prolonged or severe infusion-related reaction or following a life-threatening infusion-related reaction, dinutuximab therapy should be permanently discontinued.1
If moderate or severe capillary leak syndrome occurs, dinutuximab therapy should be interrupted immediately.1 Once the toxicity has resolved, the infusion may be resumed but the rate of infusion should be reduced by 50%.1 (See Capillary Leak Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
If life-threatening capillary leak syndrome occurs, dinutuximab therapy should be discontinued for the current cycle.1 Once the toxicity has resolved, the rate of infusion should be reduced by 50% for subsequent cycles.1 If life-threatening capillary leak syndrome recurs, dinutuximab therapy should be permanently discontinued.1
If symptomatic hypotension, systolic blood pressure less than the lower limit of normal (LLN) for age, or a reduction in systolic blood pressure by more than 15% compared with baseline occurs, therapy with dinutuximab should be interrupted.1 Once the toxicity has resolved, the infusion may be resumed but the rate of infusion should be reduced by 50%.1 If blood pressure remains stable for at least 2 hours, the infusion rate may be increased as tolerated up to a maximum infusion rate of 1.75 mg/m2 per hour.1 (See Hypotension under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
If severe systemic infection or sepsis occurs, dinutuximab therapy should be interrupted until the infection resolves.1 (See Infectious Complications under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
In patients with dilated pupils with sluggish light reflex or other visual disturbances that do not cause vision loss, dinutuximab therapy should be withheld until resolution.1 If continued therapy is warranted, the dinutuximab dosage should be reduced by 50%.1 (See Ocular Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Following a second episode of ocular toxicity, dinutuximab therapy should be permanently discontinued.1
If ocular toxicity is accompanied by visual impairment, dinutuximab therapy should be permanently discontinued.1
If severe pain occurs, the rate of infusion should be reduced to 0.875 mg/m2 per hour.1 If pain persists despite optimal medical management and reduction of the infusion rate, dinutuximab therapy should be discontinued.1 (See Pain under Warnings/Precautions: Warnings, in Cautions.)
There are no special population dosage recommendations at this time.1 Dinutuximab has not been studied in patients with hepatic or renal impairment or in geriatric patients.1
Dinutuximab is contraindicated in patients with a history of anaphylaxis to the drug.1
Serious infusion-related reactions have been reported in patients receiving dinutuximab.1, 2 Serious infusion-related reactions including facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension requiring urgent intervention (i.e., blood pressure support, bronchodilator or corticosteroid therapy, a reduction in the infusion rate, temporary interruption or permanent discontinuance of dinutuximab therapy) may occur.1 Infusion-related reactions generally have occurred during or within 24 hours following completion of the dinutuximab infusion.1 Infusion-related reactions and hypersensitivity reactions have been indistinguishable in some patients.1 In the principal efficacy study in pediatric patients with high-grade neuroblastoma, grade 3 or 4 infusion-related reactions or serious urticaria occurred in 26 or 13%, respectively, of patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with 1 or 0%, respectively, of those receiving isotretinoin alone.1 Serious adverse reactions that were consistent with anaphylaxis and required permanent discontinuance of dinutuximab therapy occurred in 2 of 134 dinutuximab-treated patients.1 In another clinical study, death from cardiac arrest occurred in 1 of 783 patients within 24 hours of dinutuximab administration.1
Patients should be monitored closely for signs of infusion reactions during and for at least 4 hours following each dinutuximab infusion in a setting where resuscitation equipment and agents necessary to treat infusion-related reactions are readily available.1 To minimize the risk of infusion-related reactions, patients receiving dinutuximab should receive IV fluids and premedication with an antihistamine, analgesic, and antipyretic prior to each infusion of the drug.1 (See Dosage and Administration: General.) If infusion-related reactions occur, reduction in infusion rate or temporary or permanent discontinuance of dinutuximab may be required.1 (See Infusion-related Reactions under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) For patients experiencing a life-threatening infusion-related reaction, the manufacturer recommends permanent discontinuance of therapy.1 Appropriate treatment and supportive care should be provided for severe, prolonged, or life-threatening infusion-related reactions.1
Peripheral neuropathy has been reported in patients receiving dinutuximab.1, 2 (See Description.) In the principal efficacy study in pediatric patients with high-grade neuroblastoma, grade 3 peripheral sensory and motor neuropathy each occurred in 1% of patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with none of those receiving isotretinoin alone.1 In another clinical study, peripheral sensory or motor neuropathy of any grade occurred in 9 or 0%, respectively, of dinutuximab-treated patients; the median duration of peripheral sensory neuropathy was 9 days (range: 3-163 days).1
In a study of a similar anti-glycolipid disialoganglioside (anti-GD2) monoclonal antibody in adults with metastatic melanoma, severe peripheral motor neuropathy occurred in 2 of 12 patients.1 One patient experienced lower extremity weakness resulting in an inability to ambulate that persisted for approximately 6 weeks.1 The other patient experienced neurogenic bladder, which persisted for approximately 3 weeks, and lower extremity weakness resulting in an inability to ambulate without assistance, which persisted for approximately 16 weeks; complete resolution of peripheral motor neuropathy was not documented in this patient.1
Dinutuximab should be permanently discontinued in patients who develop grade 2 peripheral motor neuropathy, grade 3 peripheral sensory neuropathy that interferes with daily activities for more than 2 weeks, or grade 4 peripheral sensory neuropathy.1
Pain despite premedication with analgesics, including IV morphine sulfate, occurs commonly in dinutuximab-treated patients and was reported in 85% of patients receiving the drug in the principal efficacy study in pediatric patients with high-grade neuroblastoma; abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal chest pain, and arthralgia were most commonly reported.1, 2 Grade 3 pain was reported in 51% of patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with 5% of those receiving isotretinoin alone.1 Grade 3 or 4 pain occurred more frequently during administration of dinutuximab in cycle 1 and often subsided during subsequent cycles.2, 5
To reduce pain during administration of dinutuximab, patients should receive premedication with analgesics, including an IV opiate analgesic initiated prior to each dinutuximab infusion and continued until 2 hours following completion of the infusion.1 (See Dosage and Administration: General.) If severe pain occurs, the infusion rate of dinutuximab should be reduced.1 (See Pain under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Dinutuximab should be discontinued if pain persists despite reduction of the infusion rate and optimal pain management.1
Other Warnings and Precautions
Capillary leak syndrome has been reported in patients receiving dinutuximab during any treatment cycle, but has occurred more commonly during cycles containing IL-2.1, 2, 5, 10 In the principal efficacy study in pediatric patients with high-grade neuroblastoma, grade 3-5 capillary leak syndrome occurred in 23% of patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with none of those receiving isotretinoin alone.1
If capillary leak syndrome occurs, supportive treatment (i.e., respiratory support, albumin replacement therapy)5 should be provided.1 Temporary interruption of dinutuximab therapy followed by a reduction in the infusion rate or discontinuance of therapy may be necessary depending on the severity of the toxicity.1 (See Capillary Leak Syndrome under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Hypotension has been reported in patients receiving dinutuximab.1, 2 In the principal efficacy study in pediatric patients with high-risk neuroblastoma, grade 3 or 4 hypotension occurred in 16% of patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with none of those receiving isotretinoin alone.1
Blood pressure should be closely monitored during therapy.1 Adequate IV fluids should be administered immediately before each dinutuximab infusion.1 (See Dosage and Administration: General.) In patients who develop symptomatic hypotension, systolic blood pressure less than the lower limit of normal (LLN) for age, or a reduction in systolic blood pressure by more than 15% compared with baseline, supportive treatment should be provided.1 Temporary interruption of dinutuximab therapy followed by a reduction in the infusion rate or discontinuance of therapy may be necessary if hypotension occurs during therapy with the drug.1 (See Hypotension under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Serious infections, such as bacteremia and sepsis, have been reported in patients receiving dinutuximab.1 In the principal efficacy study in pediatric patients with high-risk neuroblastoma, grade 3 or 4 bacteremia requiring urgent medical intervention (i.e., IV antibiotics) or sepsis occurred in 13 or 18%, respectively, of patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with 5 or 9%, respectively, of those receiving isotretinoin alone.1
Patients should be monitored for signs and symptoms of systemic infection.1 If a systemic infection develops, dinutuximab therapy should be temporarily interrupted until the infection has resolved.1
Adverse ocular effects including blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema have occurred in patients receiving dinutuximab.1 Ocular effects generally have resolved over time.5 In the principal efficacy study in pediatric patients with high-risk neuroblastoma, blurred vision occurred in 2% of patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with none of those receiving isotretinoin alone.1 Diplopia, mydriasis, and unequal pupillary size were reported rarely in the dinutuximab treatment group.1 In a noncomparative study evaluating the safety of dinutuximab in combination with GM-CSF, IL-2, and isotretinoin, ocular disorders were reported in 15% of patients with a median duration of 4 days (range: 0-221 days) among those with documented resolution.1
In patients who develop ocular toxicities, temporary interruption of therapy followed by dosage reduction or drug discontinuance may be required.1 (See Ocular Effects under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Severe thrombocytopenia, anemia, neutropenia, and febrile neutropenia have been reported in patients receiving dinutuximab.1 In the principal efficacy study in pediatric patients with high-risk neuroblastoma, grade 3 or 4 thrombocytopenia, anemia, neutropenia, or febrile neutropenia occurred in 39, 34, 34, or 4%, respectively, of patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with 25, 16, 13, or 0%, respectively, of those receiving isotretinoin alone.1
Peripheral blood cell counts should be monitored closely during therapy.1
Electrolyte abnormalities (i.e., hyponatremia, hypokalemia, hypocalcemia) have been reported in patients receiving dinutuximab.1 In the principal efficacy study in pediatric patients with high-risk neuroblastoma, grade 3 or 4 hypokalemia or hyponatremia occurred in 37 or 23%, respectively, of patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin compared with 2 or 4%, respectively, of those receiving isotretinoin alone.1 In a study of a similar anti-GD2 monoclonal antibody in adults with metastatic melanoma, severe hyponatremia caused by syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occurred in 2 of 12 patients.1
Serum electrolytes should be monitored daily during therapy.1 If grade 4 hyponatremia occurs despite appropriate fluid management, dinutuximab therapy should be permanently discontinued.1
Atypical Hemolytic Uremic Syndrome
Hemolytic uremic syndrome occurring in the absence of a documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension has been reported in 2 patients, approximately 4 days following the first treatment cycle, in an expanded access study.1, 10 Hemolytic uremic syndrome recurred following reinitiation of dinutuximab in one patient.1
In patients who develop hemolytic uremic syndrome, dinutuximab therapy should be permanently discontinued and appropriate treatment should be provided.1
Fetal/Neonatal Morbidity and Mortality
Dinutuximab may cause fetal harm if administered to pregnant women.1 A linear relationship between placental transfer of human immunoglobulin G (IgG) and gestational age appears to exist;4, 12 therefore, fetal exposure to dinutuximab may be highest during the third trimester of pregnancy.1
Pregnancy should be avoided during dinutuximab therapy.1 Women of childbearing potential should be advised to use an effective method of contraception while receiving dinutuximab and for at least 2 months after discontinuance of therapy.1 Patients should be apprised of the potential hazard to the fetus if the drug is used during pregnancy.1
As with all therapeutic proteins, there is a potential for immunogenicity.1 In clinical studies, anti-dinutuximab antibody formation occurred in 16.8% of patients receiving dinutuximab.1 Neutralizing antibodies were detected in 3.6% of patients who tested positive for anti-dinutuximab antibodies.1
Dinutuximab may cause fetal harm if administered to pregnant women based on its mechanism of action.1 The effects of dinutuximab may be greater during the third trimester of pregnancy.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
It is not known whether dinutuximab is distributed into human milk; however, human IgG is distributed into milk.1 Because of the potential for serious adverse reactions to dinutuximab in nursing infants, women should be advised to discontinue nursing during dinutuximab therapy.1 Women may begin nursing 6 months after discontinuance of therapy.5 The effects of the drug on nursing infants or on the production of human milk are unknown.1
Safety and efficacy of dinutuximab have not been established in infants younger than 11 months of age.1
Safety and efficacy of dinutuximab have not been established in geriatric patients.1
Pharmacokinetics of dinutuximab have not been evaluated in patients with hepatic impairment.1
Pharmacokinetics of dinutuximab have not been evaluated in patients with renal impairment.1
Adverse effects reported in 25% or more of patients receiving dinutuximab in combination with sargramostim, aldesleukin, and isotretinoin include pain,1, 2 pyrexia,1, 2 thrombocytopenia,1 lymphopenia,1 infusion-related reactions,1, 2 hypotension,1 hyponatremia,1 elevated aminotransferase (i.e., AST, ALT) concentration,1 anemia,1 vomiting,1 diarrhea,1 hypokalemia,1, 2 capillary leak syndrome,1 neutropenia,1 urticaria,1 hypoalbuminemia,1 hypocalcemia,1 and infection.2
No formal drug interaction studies have been performed to date.1
Concomitant immunosuppressive therapy may interfere with the mechanism of action of dinutuximab.1, 5 Patients requiring concomitant therapy with systemic corticosteroids or other immunosuppressive agents were excluded from the principal efficacy study of dinutuximab in pediatric patients with high-grade neuroblastoma.1 Concomitant use of systemic corticosteroids with dinutuximab is not recommended5 unless required for the management of toxicity (e.g., serious hypersensitivity or infusion-related reactions).1, 5, 10
Immune globulin IV also may interfere with the mechanism of action of dinutuximab and should not be administered within 2 weeks before or 1 week after each course of dinutuximab.5, 10
Dinutuximab, a chimeric human-murine anti-glycolipid disialoganglioside (anti-GD2) monoclonal antibody, is an antineoplastic agent.1, 2, 6, 7, 11 The drug is an IgG1 kappa immunoglobulin.1, 6, 7, 11 Dinutuximab is selective for GD2,5 a glycolipid minimally expressed on the surface of normal cells of neuroectodermal origin, including central neurons, peripheral nerve fibers, and melanocytes.1, 2, 5, 8, 11 Overexpression of GD2 has been identified in several malignancies, including neuroblastoma and most melanomas.1, 2, 5, 6, 8, 11 Following binding of dinutuximab to antigen GD2, cell lysis occurs through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).1, 5, 6, 7 In the presence of human effector cells, including peripheral blood mononuclear cells (PBMCs) and granulocytes, dinutuximab has demonstrated dose-dependent cytotoxicity of neuroblastoma cells; enhanced cell lysis has been observed with the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2).5, 7, 11 Dinutuximab also has been shown to reduce tumor growth of GD2-expressing cell lines in xenograft models.7
Nonclinical studies suggest that dinutuximab-induced peripheral neuropathy may be a pharmacologic consequence of dinutuximab binding to antigen GD2 on the surface of peripheral nerve fibers and/or myelin.1, 5, 7, 8 Decreases in mechanical pain thresholds have been demonstrated in animal studies beginning shortly after administration of anti-GD2 monoclonal antibodies, including dinutuximab, and persisting for up to 48 hours after completion of drug administration.7 (See Peripheral Neuropathy and also see Pain under Warnings/Precautions: Warnings, in Cautions.)
The elimination half-life of dinutuximab is 10 days.1
Risk of serious infusion-related reactions and anaphylaxis.1 Importance of informing clinician immediately if signs and symptoms of such reactions, including facial swelling, urticaria, breathing difficulty, and lightheadedness or dizziness, occur during or within 24 hours of an infusion of the drug.1
Risk of severe pain and peripheral sensory and motor neuropathy.1 Importance of promptly informing clinician if severe or worsening pain or signs and symptoms of neuropathy (e.g., numbness, tingling, burning, weakness) occur.1
Risk of capillary leak syndrome.1 Importance of informing clinician immediately if signs and symptoms of capillary leak syndrome (e.g., hypotension, generalized edema, dyspnea) occur.1, 5
Risk of hypotension during infusion of the drug.1 Importance of informing clinician immediately if signs and symptoms of hypotension occur.1
Risk of infection.1 Importance of informing clinician immediately if signs and symptoms of infection occur.1
Risk of adverse ocular effects.1 Importance of promptly informing clinician if signs and symptoms of ocular toxicity (e.g., blurred vision, photophobia, ptosis, diplopia, unequal pupil size) occur.1
Risk of myelosuppression.1 Importance of promptly informing clinician if signs and symptoms of anemia, thrombocytopenia, or infection occur.1
Risk of electrolyte abnormalities (i.e., hypokalemia, hyponatremia, hypocalcemia).1 Importance of informing clinician if signs and symptoms of electrolyte abnormalities (e.g., seizures, palpitations, muscle cramping) occur.1
Risk of atypical hemolytic uremic syndrome.1 Importance of informing clinician if signs and symptoms of hemolytic uremic syndrome (e.g., fatigue, dizziness, fainting, pallor, edema, decreased urination, hematuria) occur.1
Risk of fetal harm.1 Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving the drug and for at least 2 months after discontinuance of therapy.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1
Importance of advising women not to breast-feed during therapy.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of dinutuximab is restricted.9 (See Restricted Distribution Program under Dosage and Administration: General.)
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection concentrate, for IV infusion | 3.5 mg/mL |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions April 4, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. United Therapeutics. Unituxin® (dinutuximab) injection for intravenous infusion prescribing information. Silver Spring, MD; 2015 Mar.
2. Yu AL, Gilman AL, Ozkaynak MF et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med . 2010; 363:1324-34. [PubMedCentral][PubMed 20879881]
3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2015 Oct 27. [Web]
4. Simister NE. Placental transport of immunoglobulin G. Vaccine . 2003; 21:3365-9. [PubMed 12850341]
5. United Therapeutics Europe. Unituxin® (dinutuxiimab) injection for intravenous infusion. Annex I: Summary of product characteristics. Surrey, United Kingdom. (undated).
6. Dhillon S. Dinutuximab: first global approval. Drugs . 2015; 75:923-7. [PubMed 25940913]
7. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125516Orig1s000: Pharmacology Review(s). From FDA website. [Web]
8. Mackall CL, Merchant MS, Fry TJ. Immune-based therapies for childhood cancer. Nat Rev Clin Oncol . 2014; 11:693-703. [PubMed 25348789]
9. United Therapeutics. Ordering and distribution information. 2015 Oct. From United Therapeutics for US Healthcare Professionals website. [Web]
10. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125516Orig1s000: Medical Review(s). From FDA website. [Web]
11. Gilman AL, Ozkaynak MF, Matthay KK et al. Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children's Oncology Group. J Clin Oncol . 2009; 27:85-91. [PubMed 19047298]
12. Pitcher-Wilmott RW, Hindocha P, Wood CB. The placental transfer of IgG subclasses in human pregnancy. Clin Exp Immunol . 1980; 41:303-8. [PubMedCentral][PubMed 7438556]
13. United Therapeutics, Silver Spring, MD: Personal communication.