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  • CLASSES

    Antineoplastic Monoclonal Antibodies

    BOXED WARNING

    Infusion-related reactions

    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.

    Neuropathic pain, peripheral neuropathy

    Severe neuropathic pain and sensory and motor peripheral neuropathy have 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.

    DEA CLASS

    Rx

    DESCRIPTION

    Anti-GD2 monoclonal antibody
    Indicated in combination with sargramostim, aldesleukin, and 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
    Life-threatening infusion-related reactions including anaphylaxis have occurred; administer hydration and premedicate with IV diphenhydramine and oral acetaminophen prior to each infusion

    COMMON BRAND NAMES

    Unituxin

    HOW SUPPLIED

    Unituxin Intravenous Inj Sol: 1mL, 3.5mg

    DOSAGE & INDICATIONS

    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).

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dinutuximab has not been evaluated in patients with hepatic impairment. Specific guidelines for dosage adjustments in hepatic impairment are not available.

    Renal Impairment

    Dinutuximab has not been evaluated in patients with renal impairment. Specific guidelines for dosage adjustments in renal impairment are not available.

    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 reconstitution: refrigerate the diluted solution (2 to 8 degrees Celsius; 36 to 46 degrees Fahrenheit) 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.

    STORAGE

    Unituxin:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Store in carton
    - Store in original carton in refrigerator (35 to 46 degrees F) until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Infusion-related reactions

    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.

    Neuropathic pain, peripheral neuropathy

    Severe neuropathic pain and sensory and motor peripheral neuropathy have 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.

    Hypotension

    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.

    Infection, sepsis

    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.

    Ocular disease, papilledema, visual disturbance

    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.

    Anemia, neutropenia, thrombocytopenia

    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.

    Electrolyte imbalance, hypocalcemia, hypokalemia, hyponatremia

    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.

    Hemolytic-uremic syndrome

    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

    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.

    Respiratory insufficiency

    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.

    Hepatic disease

    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.

    Renal disease, renal impairment

    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

    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.

    Pregnancy

    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.

    Breast-feeding

    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.

    Contraception requirements, reproductive risk

    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.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 34.0-63.0
    angioedema / Rapid / 0-60.0
    bronchospasm / Rapid / 0-60.0
    lymphopenia / Delayed / 51.0-51.0
    myalgia / Early / 0-51.0
    arthralgia / Delayed / 0-51.0
    bone pain / Delayed / 0-51.0
    abdominal pain / Early / 0-51.0
    musculoskeletal pain / Early / 0-51.0
    chest pain (unspecified) / Early / 0-51.0
    back pain / Delayed / 0-51.0
    neuropathic pain / Delayed / 0-51.0
    thrombocytopenia / Delayed / 39.0-49.0
    anemia / Delayed / 34.0-46.0
    hypokalemia / Delayed / 37.0-41.0
    fever / Early / 40.0-40.0
    capillary leak syndrome / Early / 40.0-40.0
    hyponatremia / Delayed / 23.0-36.0
    infusion-related reactions / Rapid / 25.0-25.0
    dyspnea / Early / 0-25.0
    elevated hepatic enzymes / Delayed / 8.0-23.0
    disseminated intravascular coagulation (DIC) / Delayed / 0-17.0
    GI bleeding / Delayed / 0-17.0
    hematemesis / Delayed / 0-17.0
    hypotension / Rapid / 16.0-16.0
    infection / Delayed / 16.0-16.0
    papilledema / Delayed / 0-15.0
    diarrhea / Early / 13.0-13.0
    urticaria / Rapid / 13.0-13.0
    hypoxia / Early / 12.0-12.0
    anorexia / Delayed / 10.0-10.0
    hypoalbuminemia / Delayed / 7.0-8.0
    hypophosphatemia / Delayed / 6.0-8.0
    hypocalcemia / Delayed / 7.0-7.0
    hyperglycemia / Delayed / 6.0-6.0
    vomiting / Early / 6.0-6.0
    hematuria / Delayed / 0-6.0
    bleeding / Early / 6.0-6.0
    hematoma / Early / 0-6.0
    epistaxis / Delayed / 0-6.0
    peripheral neuropathy / Delayed / 3.0-3.0
    hypomagnesemia / Delayed / 2.0-2.0
    nausea / Early / 2.0-2.0
    hypertension / Early / 2.0-2.0
    sinus tachycardia / Rapid / 2.0-2.0
    SIADH / Delayed / 0-1.0
    hypertriglyceridemia / Delayed / 1.0-1.0
    hemolytic-uremic syndrome / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / 1.0-1.0
    cardiac arrest / Early / 0.1-0.1
    myelitis / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    seizures / Delayed / Incidence not known

    Moderate

    proteinuria / Delayed / 16.0-66.0
    antibody formation / Delayed / 3.6-18.0
    edema / Delayed / 17.0-17.0
    wheezing / Rapid / 15.0-15.0
    blurred vision / Early / 2.0-15.0
    photophobia / Early / 0-15.0
    urinary retention / Early / Incidence not known
    urinary incontinence / Early / Incidence not known

    Mild

    nasal congestion / Early / 20.0-20.0
    diplopia / Early / 0-15.0
    ptosis / Delayed / 0-15.0
    mydriasis / Early / 0-15.0
    weight gain / Delayed / 10.0-10.0
    paresthesias / Delayed / Incidence not known
    weakness / Early / Incidence not known
    lethargy / Early / Incidence not known
    headache / Early / Incidence not known

    DRUG INTERACTIONS

    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    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.