dinutuximab (Rx)

Brand and Other Names:Unituxin
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Dosing & Uses

AdultPediatric

Not indicated

Dosage Forms & Strengths

solution for injection

  • 17.5mg/5mL (3.5mg/mL)

Neuroblastoma

Indicated in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA) for pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-time multiagent, multimodality therapy

17.5 mg/m²/day IV over 10-20 hr for 4 consecutive days for maximum of 5 cycles

Cycles 1, 3, and 5 (24 days' duration): Administer dinutuximab on days 4, 5, 6, and 7

Cycles 2 and 4 (32 days' duration): Administer dinutuximab on days 8, 9, 10, and 11

Initiate at infusion rate of 0.875 mg/m²/hr for 30 min; may gradually increase infusion rate, as tolerated, to maximum of 1.75 mg/m²/hr

Administration

Verify that patient has adequate hematologic, respiratory, hepatic, and renal function prior to initiating each course of dinutuximab

Not for administration as intravenous push or bolus

Pretreatment and guidelines for pain management

  • Intravenous hydration
    • Administer 0.9% NaCl injection, USP 10 mL/kg intravenous infusion over 1 hr just prior to initiating each dinutuximab infusion
  • Analgesics
    • Morphine sulfate (50 mcg/kg) IV immediately prior to initiation of dinutuximab; continue as drip at infusion rate of 20-50 mcg/kg/hr during and for 2 hr following completion of dinutuximab
    • Administer additional 25-50 mg/kg IV morphine sulfate doses PRN for pain up to once q2hr followed by increase in morphine sulfate infusion rate in clinically stable patients
    • May use fentanyl or hydromorphone if morphine sulfate not tolerated
    • If pain inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with intravenous morphine
  • Antihistamines and antipyretics
    • Administer antihistamine such as diphenhydramine (0.5-1 mg/kg; not to exceed 50 mg) IV over 10-15 min starting 20 min prior to initiation of dinutuximab and as tolerated q4-6hr during dinutuximab infusion
    • Administer acetaminophen (10-15 mg/kg; not to exceed 650 mg) 20 min prior to each dinutuximab infusion and q4-6hr PRN for fever or pain; administer ibuprofen (5-10 mg/kg) q6hr PRN for control of persistent fever or pain

Dosage Modifications

Adverse reactions requiring permanent therapy discontinuation

  • Grade 3 or 4 anaphylaxis
  • Grade 3 or 4 serum sickness
  • Grade 3 pain unresponsive to maximum supportive measures
  • Grade 4 sensory neuropathy or grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks
  • Grade 2 peripheral motor neuropathy
  • Subtotal or total vision loss
  • Grade 4 hyponatremia despite appropriate fluid management

Dose modifications for selected adverse reactions

  • Mild-to-moderate adverse reactions include transient rash, fever, rigors, and localized urticaria
    • Onset of reaction: Reduce infusion rate to 50% of previous rate; monitor closely
    • After resolution: Gradually increase infusion rate up to maximum rate of 1.75 mg/m²/hr
  • Prolonged or severe adverse reactions including mild bronchospasm without other symptoms or angioedema that does not affect airway
    • Onset of reaction: Interrupt therapy immediately
    • After resolution: Resume dinutuximab at 50% of previous rate and monitor if signs and symptoms resolve rapidly
  • First recurrence
    • Discontinue therapy until following day; if symptoms resolve and continued therapy necessary, premedicate with hydrocortisone 1 mg/kg (maximum dose 50 mg) IV and administer dinutuximab at rate of 0.875 mg/m²/hr in an intensive care unit
  • Second recurrence
    • Permanently discontinue therapy

Capillary leak syndrome

  • Moderate-to-severe but not life-threatening capillary leak syndrome
    • Onset of reaction: Interrupt therapy immediately
    • After resolution: Resume dinutuximab infusion at 50% of previous rate
  • Life-threatening capillary leak syndrome
    • Onset of action: Discontinue therapy for current cycle
    • After resolution: In subsequent cycles, administer dinutuximab infusion at 50% of previous rate

Hypotension requiring medical intervention

  • Symptomatic hypotension, systolic blood pressure (SBP) less than lower limit of normal for age, or SBP decreased by more than 15% compared with baseline
  • Onset of reaction: Interrupt therapy immediately
  • After resolution: Resume dinutuximab infusion at 50% of previous rate; if blood pressure remains stable for at least 12 hr, increase infusion rate as tolerated to maximum rate of 1.75 mg/m&sup2/hr

Severe systemic infection or sepsis

  • Onset of reaction: Discontinue dinutuximab until resolution of infection and proceed with subsequent cycles of therapy

Neurological disorder of the eye

  • Onset of reaction: Discontinue dinutuximab infusion until resolution
  • After resolution: Reduce dinutuximab dose by 50%
  • First recurrence or if accompanied by visual impairment: Permanently discontinue therapy
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Adverse Effects

>10% (All Grades)

Dinutuximab/retinoic acid group

Pain (85%)

Pyrexia (72%)

Edema (17%)

Thrombocytopenia (66%)

Lymphopenia (62%)

Anemia (51%)

Neutropenia (39%)

Hypotension (60%)

Capillary leak syndrome (40%)

Hemorrhage (17%)

Hypertension (14%)

Hyponatremia (58%)

Hypokalemia (43%)

Hypoalbuminemia (33%)

Hypocalcemia (27%)

Hypophosphatemia (20%)

Hyperglycemia (18%)

Hypertriglyceridemia (16%)

Decreased appetite (15%)

Hypomagnesemia (12%)

Increased alanine aminotransferase (56%)

Increased aspartate aminotransferase (28%)

Increased serum creatinine (15%)

Increased weight (10%)

Vomiting (46%)

Diarrhea (43%)

Nausea (10%)

Urticaria (37%)

Hypoxia (24%)

Tachycardia (19%)

Sepsis (18%)

Device-related infection (16%)

Proteinuria (16%)

Peripheral neuropathy (13%)

Postmarketing Reports

Neurotoxicity, including pain, peripheral neuropathy

Neurological disorders of the eye

Prolonged urinary retention

Transverse myelitis

Reversible posterior leukoencephalopathy syndrome

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Warnings

Black Box Warning

Infusion reactions

  • Serious and potentially life-threatening infusion reactions occurred in 26% of patients
  • Administer required prehydration and premedication, including antihistamines, prior to each dinutuximab infusion
  • Monitor closely for signs and symptoms of an infusion reaction during and for at least 4 hr following completion of each dinutuximab infusion
  • Immediately interrupt therapy for severe infusion reactions and permanently discontinue dinutuximab for anaphylaxis

Neurotoxicity

  • Causes severe neuropathic pain in the majority of patients
  • Administer intravenous opioid prior to, during, and for 2 hr following completion of the infusion
  • In clinical studies of patients with high-risk neuroblastoma, grade 3 peripheral sensory neuropathy occurred in 2-9% of patients
  • In clinical studies of dinutuximab and related GD2-binding antibodies, severe motor neuropathy was observed in adults
  • Resolution of motor neuropathy was not documented in all cases
  • Discontinue for severe unresponsive pain, severe sensory neuropathy, or moderate-to-severe peripheral motor neuropathy

Contraindications

Hypersensitivity

Cautions

Infusion reactions may occur; prior to dinutuximab infusion, administer required intravenous hydration and premedication with antihistamines, analgesics, and antipyretics and monitor for signs and symptoms of infusion reactions during and for at least 4 hr following completion of each infusion in a setting where cardiopulmonary resuscitation medication and equipment is available

Abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal pain, and arthralgia reported in dinutuximab/retinoic acid treated group; premdicate with analgesics, including IV opioids, prior to each dose of dinutuximab and continue until 2 hr following completion of dinutuximab; for severe pain, decrease dinutuximab infusion rate to 0.875 mg/m&sup2/hr; discontinue therapy if pain is not adequately controlled despite infusion rate reduction and institution of maximum supportive measures

Permanently discontinue therapy in patients with grade 2 peripheral motor neuropathy, grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks, or grade 4 sensory neuropathy

Immediately interrupt or discontinue therapy and institute supportive management in patients with symptomatic or severe capillary leak syndrome

Closely monitor blood pressure during treatment; immediately interrupt or discontinue therapy and institute supportive management in patients with symptomatic hypotension, systolic blood pressure less than lower limit of normal for age, or systemic blood pressure that is decreased by more than 15% compared with baseline

Monitor patients for signs and symptoms of systemic infection and temporarily discontinue therapy in patients who develop systemic infection until resolution of infection

Interrupt therapy in patients experiencing dilated pupil with sluggish light reflex or other visual disturbances that do not cause visual loss; upon resolution and if continued treatment with therapy is necessary, decrease dinutuximab dose by 50%; permanently discontinue therapy in patients with recurrent signs of eye disorder following dose reduction and patients who experience vision loss

Bone marrow suppression reported; monitor peripheral blood cell counts closely during therapy

Electrolyte abnormalities reported; monitor serum electrolytes daily during therapy

Atypical hemolytic uremic syndrome reported; permanently discontinue therapy and institute supportive management for signs of the syndrome

Advise pregnant women of the potential risk to a fetus; advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of dinutuximab

Urinary retention that persists for weeks to months following discontinuation of opioids reported; permanently discontinue therapy in patients with urinary retention that does not resolve following discontinuation of opioids

Transverse myelitis reported; promptly evaluate any patient with signs or symptoms of transverse myelitis such as weakness, paresthesia, sensory loss, or incontinence; permanently discontinue therapy in patients who develop transverse myelitis

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) reported; institute appropriate medical treatment and permanently discontinue therapy in patients with signs and symptoms of RPLS (e.g., severe headache, hypertension, visual changes, lethargy, or seizures)

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Pregnancy & Lactation

Pregnancy

Studies in pregnant women and reproductive studies in animals have not been performed; monoclonal antibodies are transported across placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester; advise pregnant women of potential risk to a fetus; advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of dinutuximab  

Lactation

Unknown whether distributed in breast milk; potential for serious adverse reactions in a breastfed infant; advise nursing mother to discontinue breastfeeding during therapy

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

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Pharmacology

Mechanism of Action

Chimetic monoclonal antibody that binds to the glycolipid disialoganglioside (GD2). GD2 is a glycolipid expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including central nervous system and peripheral nerves

Dinutuximab binds to cell surface GD2 and induces lysis of GD2-expressing cells through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity

Absorption

Peak plasma concentration: 11.5 mcg/mL

Distribution

Vd: 5.4 L

Elimination

Half-life: 10 days

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Administration

IV Preparation

Inspect visually for particulate matter and discoloration prior to administration

Discard the vial if the solution is cloudy, has pronounced discoloration, or contains particulate matter

Aseptically withdraw the required volume of dinutuximab from the single-use vial and inject into a 100 mL bag of 0.9% NaCl injection, USP

Mix by gentle inversion; do NOT shake

Discard unused contents of the vial

Storage

Store vials under refrigeration at 2-8°C until time of use

Do not freeze or shake the vial

Keep vial in outer carton to protect from light

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Formulary

FormularyPatient Discounts

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Adding plans allows you to:

  • View the formulary and any restrictions for each plan.
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  • Compare formulary status to other drugs in the same class.
  • Access your plan list on any device – mobile or desktop.

The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
QL Quantity Limits
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
ST Step Therapy
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
OR Other Restrictions
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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