Dinutuximab (Unituxin) is a chemotherapeutic antineoplastic drug that is used to treat children with high-risk neuroblastoma.

Indications of Dinutuximab (Unituxin):

• Neuroblastoma:

  • It is useful for the treatment of high-risk neuroblastoma (in combination with granulocyte-macrophage colony-stimulating factor [GM-CSF; sargramostim], interleukin-2 [IL-2; aldesleukin] and 13-cis-retinoic acid [RA; isotretinoin]) in pediatric patients who achieve at least a partial response to prior first-line multiagent, multimodality therapy.

Use in Adults:

Not indicated

Dinutuximab dose in children:

Note:

• Before therapy, intravenous hydration and premedication with analgesics, antihistamines, and antipyretics are necessary.
• Hematologic, respiratory, hepatic, and renal function should be checked before each cycle of therapy.

Dinutuximab (Unituxin) Dose in the treatment of high-risk Neuroblastoma:

• Infants, Children, and Adolescents:

  • 17.5 mg/m²/day IV for 4 consecutive days for a maximum of 5 cycles (in combination with GM-CSF [sargramostim], IL-2 [aldesleukin] and 13-cis-retinoic acid [isotretinoin]).
  • Infuse on days 4, 5, 6, and 7 during cycles 1, 3, and 5 (cycles 1, 3, and 5 are 24 days in duration);
  • infuse on days 8, 9, 10, and 11 during cycles 2 and 4 (cycles 2 and 4 are 32 days in duration).
  • In the reported trials, the youngest patient was 11 months of age.

  • Premedications:

    • IV hydration: Normal saline 10 ml/kg infused over 1 hour just before each dinutuximab infusion.
    • Antihistamine: Diphenhydramine:0.5 to 1 mg/kg/dose IV
    • The maximum dose: 50 mg/dose; administer over 10 to 15 minutes starting 20 minutes before dinutuximab infusion and every 4 to 6 hours as tolerated during the infusion.
    • Antiemetics: These should be given to prevent nausea and vomiting due to the moderate emetic potential of dinutuximab.
    • Antipyretics: Acetaminophen: 10 to 15 mg/kg/dose per oral; administer 20 minutes before each infusion and every 4 to 6 hours as needed for fever and pain.
      • The maximum dose: 650 mg/dose.
      • Ibuprofen: 5 to 10 mg/kg/dose per oral every 6 hours as needed for control of persistent fever or pain.
      • The maximum dose: 400 mg/dose.
    • Analgesics: Morphine: 50 mcg/kg IV, administer immediately before dinutuximab infusion initiation; continue as a morphine drip at a rate of 20 to 50 mcg/kg/hour during and for 2 hours following completion of dinutuximab infusion.
    • May administer additional morphine doses of 25 to 50 mcg/kg IV as needed up to once every 2 hours followed by an increase in the drip rate in clinically stable patients. Fentanyl or hydromorphone can be given if morphine is not tolerated.
    • Adjunct therapy with gabapentin or lidocaine should be given if the pain is not controlled with opioids.

Dinutuximab (Unituxin) Dosing adjustment for toxicity:

• Infants, Children, and Adolescents:

  • Anaphylaxis, grade 3 or 4: Permanently discontinue therapy.
  • Capillary leak syndrome:
    • Moderate to severe, but not life-threatening: Immediately interrupt infusion. Once the symptoms resolve, treatment should be restarted with a 50% dose reduction.
    • Life-threatening: Discontinue infusion for the current cycle,50% dose reduction should be done in next cycle. If life-threatening capillary leak syndrome recurs, permanently discontinue therapy.
  • Hemolytic uremic syndrome: Therapy should be permanently stopped and supportive management should be given.
  • Hyponatremia, grade 4 (despite appropriate fluid management): Permanently discontinue therapy.
  • Hypotension (symptomatic hypotension, systolic blood pressure [SBP] less than the lower limit of normal for age, or SBP decreased by more than 15% compared to baseline): Interrupt infusion. Once symptoms resolve, a 50% dose reduction should be done. If blood pressure remains stable for ≥2 hours, gradually increase the infusion rate as tolerated up to a maximum rate of 1.75 mg/m²/hour.
  • Infection (systemic)/sepsis, severe: Discontinue therapy until the infection resolves; may resume therapy with subsequent cycles.
  • Infusion-related reaction:
    • Mild to moderate reaction (eg, transient rash, fever, rigors, and localized urticaria that respond promptly to symptomatic treatment):
      • 50% dose reduction and close monitoring are necessary.
      • Upon resolution, gradually increase the infusion rate up to a maximum of 1.75 mg/m²/hour.
    • Severe or prolonged reaction (eg, mild bronchospasm without other symptoms, angioedema that does not affect the airway):
      • Immediately interrupt infusion.
      • 50% dose reduction and close monitoring are necessary once symptoms resolve.
      • If reaction recurs, discontinue therapy until the following day.
      • If symptoms resolve and further treatment is warranted, premedicate with IV hydrocortisone 1 mg/kg (maximum dose: 50 mg/dose) and infuse at a rate of 0.875 mg/m²/hour in an intensive care unit.
      • If reaction recurs again, therapy should be permanently stopped.
    • Life-threatening reaction:
      • Permanently discontinue therapy and administer supportive management.
  • Neuropathy:
    • Grade 4 sensory neuropathy or grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks:
      • Permanently discontinue therapy.
    • Grade 2 or higher peripheral motor neuropathy:
      • Permanently discontinue therapy.
  • Ocular neurological disorders (eg, blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and/or papilledema):
    • Discontinue infusion until symptom resolution.
    • Once symptoms are resolved, a 50% dose reduction is necessary.
    • If reaction recurs, or if a reaction is accompanied by visual impairment (eg, subtotal or total vision loss), permanently discontinue therapy.
  • Pain, severe (grade 3): Decrease the infusion rate to 0.875 mg/m²/hour. If pain is not adequately controlled despite rate reduction and use of maximum supportive measures, permanently discontinue therapy.
  • Reversible posterior leukoencephalopathy syndrome: Permanently discontinue therapy.
  • Serum sickness, grade 3 or 4: Permanently discontinue therapy.
  • Transverse myelitis: Permanently discontinue therapy.
  • Urinary retention (persistent after opioid discontinuation): Permanently discontinue therapy.

Dinutuximab  dose in pregnancy: X

• Dinutuximab has not undergone any reproduction studies.
• The highest concentration of monoclonal antibody crosses the placenta in the last trimester.
• Dinutuximab may cause fetal harm, depending on how it works.
• Effective contraception is essential during therapy as well as for two months following the last dose.

Use of Dinutuximab while breastfeeding

• It is unknown if dinutuximab is excreted in breast milk.
• Breast milk contains IgG molecules.
• According to the manufacturer, breastfeeding is not recommended because of the risk of serious side effects for the infant.

Dinutuximab (Unituxin) Dose adjustment in renal disease:

• Infants, Children, and Adolescents:
  • There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dinutuximab (Unituxin) Dose adjustment in liver disease:

• Infants, Children, and Adolescents:
  • There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Common Side Effects of Dinutuximab (Unituxin):

• Cardiovascular:

  • Hypotension
  • Capillary Leak Syndrome
  • Tachycardia
  • Edema
  • Hypertension

• Central Nervous System:

  • Pain
  • Peripheral Neuropathy

• Dermatologic:

  • Urticaria

• Endocrine & Metabolic:

  • Hyponatremia
  • Hypokalemia
  • Hypoalbuminemia
  • Hypocalcemia
  • Hypophosphatemia
  • Hyperglycemia
  • Hypertriglyceridemia
  • Hypomagnesemia

• Gastrointestinal:

  • Increased Serum ALT
  • Vomiting
  • Diarrhea
  • Increased Serum AST
  • Decreased Appetite

• Genitourinary:

  • Proteinuria

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Lymphocytopenia
  • Anemia
  • Neutropenia
  • Hemorrhage

• Hypersensitivity:

  • Severe Infusion-Related Reaction

• Infection:

  • Sepsis
  • Infection
  • Bacteremia

• Renal:

  • Increased Serum Creatinine

• Respiratory:

  • Hypoxia

• Miscellaneous:

  • Fever
  • Infusion-Related Reaction

Rare Side Effects Of Dinutuximab:

• Central Nervous System:

  • Peripheral Sensory Neuropathy
  • Peripheral Motor Neuropathy

• Dermatologic:

  • Anaphylaxis

• Endocrine & Metabolic:

  • Weight Gain

• Gastrointestinal:

  • Nausea

• Hematologic & Oncologic:

  • Febrile Neutropenia
  • Hemolytic-Uremic Syndrome

• Ophthalmic:

  • Blurred Vision

Dinutuximab (Unituxin) Side effect (Frequency not known):

• Ophthalmic:

  • Blepharoptosis
  • Optic Nerve Damage
  • Papilledema
  • Photophobia

Contraindications to Dinutuximab (Unituxin):

• Anaphylaxis history to dinutuximab and any component of the formulations

Warnings and precautions

• Suppression of bone marrow

  • Dinutuximab has been known to cause bone marrow suppression, including severe (grades 3 or 4) anemia and neutropenia.
  • It is important to monitor your full blood count regularly.

• Capillary leak syndrome

  • Some patients may experience severe capillary leak syndrome after receiving dinutuximab therapy.
  • Capillary leak syndrome should not be treated. Instead, the patient should receive appropriate therapy.
  • It may be necessary to restart therapy with a reduction in the infusion rate or permanent withdrawal.

• An abnormality in the electrolyte:

  • In some cases, therapy can cause electrolyte imbalances, including hyponatremia and hypokalemia. Regular monitoring is therefore necessary.
  • A study of a similar anti-GD2 antibody was done.
  • It revealed that severe hyponatremia could be caused by the syndrome of inappropriate antidiuretic hormonal hormone secretion (SIADH).

• Gastrointestinal toxicities:

  • Because of the moderate emetic properties of danutuximab, antiemetic medication should be prescribed prior to therapy.

• Hemolytic uremic Syndrome:

  • Patients who received danutuximab suffered from hemolytic uremic symptoms, which can lead to anemia, electrolyte abnormalities and renal insufficiency.
  • On rechallenge, one of the patients developed atypical hemolytic-uremic syndrome.
  • Both permanent withdrawal and supportive management are required.

• Hypotension

  • Dinutuximab is known for its ability to cause severe hypotension.
  • Adequate intravenous hydration is essential before therapy. Close blood pressure monitoring is also important.
  • Patients with systolic pressure that is lower than the upper limit of normal for their age or that has fallen by more than 15% should receive appropriate medical management.

• Infection

  • Dinutuximab can often cause severe (grade 3-4) bacteremia, which may require intravenous antibiotics and other urgent intervention.
  • Patients receiving dinutuximab also developed Sepsis.
  • It is important to monitor for any signs or symptoms of systemic infections.
  • It may be necessary to seek therapy in order to stop permanent damage.

• Infusion reaction: [US Boxed Warning]

  • Some patients may experience life-threatening injection reactions.
  • It is important to get adequate hydration before starting therapy.
  • Ensure that patients are monitored closely for any signs or symptoms of an infusion reaction, at least for 4 hours after each dinutuximab injection.
  • Infusion reactions are usually experienced during or within 24 hours after completion.
  • They may include dyspnea and bronchospasm as well as stridor, urticaria and facial and upper-airway edema.
  • These should be treated with blood pressure support, bronchodilator treatment, corticosteroids and infusion rate interruption and/or decrease.
  • If you experience symptoms of infusion reactions, stop therapy immediately and discontinue all medication if you develop anaphylaxis.
  • Infusions should be performed in a facility that has cardiopulmonary medication/equipment.

• Neurotoxicity: [US Boxed Warn]

  • Therapy can help with severe neuropathic pain, peripheral neuropathy, and severe neuropathic symptoms.
  • Intranavenous opioids should not be administered before, during, or for more than 2 hours following dinutuximab injections.
  • Clinical studies on patients with high-risk neuroblastoma showed that grade 3 peripheral sensory neuropathy was found in between 2% and 9% of patients.
  • Motor neuropathy was observed in clinical trials of dinutuximab or related GD2-binding antibodies.
  • Motor neuropathy was not always resolved.
  • Therapy should be stopped if there is severe unresponsiveness, severe sensory neuropathy or severe peripheral motor neuropathy.
  • Permanently discontinue treatment for grade 2 or higher peripheral neuropathy, Grade 3 sensory nerve neuropathy that interferes for more than two weeks with daily activities, and Grade 4 sensory neuropathy.
  • Patients with peripheral sensory neuropathy of any degree experienced a median of 9 days. The range was 3-163 days.

• Ocular toxicities:

  • Clinical trials showed that neurological ocular toxicities include blurred vision, photophobia and mydriasis as well as fixed or unequal pupils, optic neuro disorder, eyelid posis and papilledema.
  • Patients who had complete resolution of their ocular toxicities experienced a median of 4 days of symptoms (range: 0 - 221 days).
  • It may be necessary to reduce dosages or withdraw from therapy.

• Pain:

  • Patients receiving dinutuximab therapy often felt pain, despite the fact that they were taking analgesic/opioid medication.
  • Infusions are often associated with pain. These include back, generalized, extremity or abdominal pain, as well as neuralgia and musculoskeletal chest pain.
  • It is important to take analgesics before, during, and 2 hours after infusions.
  • In severe pain, it might be necessary to reduce the rate of therapy withdrawal or decrease the infusion rate.

• Reversible posterior Leukoencephalopathy Syndrome:

  • With danutuximab, you can get reversible posterior leukoencephalopathy (Syndrome of severe headaches, hypertension, visual changes or seizures), as well as severe headaches, hypertension, visual problems, seizures, and lethargy.
  • These symptoms can be managed and withdrawn.

• Transverse myelitis

  • Transverse myelitis can present with weakness, paresthesia or sensory loss.
  • This condition should not be treated.

• Urinary retention

  • Dinutuximab can cause urinary retention that lasts for weeks or even months after the opioid has been discontinued.
  • If the urinary retention persists after opioid discontinuation, it is time to withdraw treatment permanently.

Dinutuximab: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Blood pressure
• CBC with differential counts
• Serum electrolytes
• Renal function tests
• Monitor for signs/symptoms of infusion reactions (during and for at least 4 hours after infusion), pain, peripheral neuropathy, capillary leak syndrome, infection/sepsis, hemolytic uremic syndrome, ocular toxicity, urinary retention, transverse myelitis, and/or reversible posterior leukoencephalopathy syndrome.

How to administer Dinutuximab (Unituxin)?

Note: Antiemetics should be given before therapy due to the moderate emetic potential of dinutuximab.

Intravenous administration:

• Before administration, the drug must be diluted.
• It should always be given as an IV infusion only; do not administer as an IV push or bolus.
• Infusion normal saline 10 mL/kg IV over 1 hour should be given before therapy in addition to premedication with analgesics, an antihistamine, and an antipyretic (see Dosing: Pediatric).
• Infuse in an environment equipped to monitor for and manage infusion reactions.
• Interrupt infusion for toxicity (see Dosing Adjustment for Toxicity).
• Dinutuximab infusion should be started at a rate of 0.875 mg/m²/hour for half-hour.
• Increase infusion rate gradually as tolerated to a maximum rate of 1.75 mg/m²/hour to infuse dose over 10 to 20 hours each day.
• Close monitoring for signs and symptoms of an infusion reaction during and for at least 4 hours following completion of each dinutuximab infusion is required.

Mechanism of action of Dinutuximab (Unituxin):

• Dinutuximab induces cell lysis (of GD2-expressing cell) via antibody-dependent cellmediated cytotoxicity, (ADCC), and complement-dependent cytotoxicity.
• It does this by binding to disialoganglioside GD2, a protein that is abundant in neuroblastoma and most melanomas.

Terminal Half-life elimination:

• 10 days

International Brand Names of Dinutuximab:

• Unituxin

Dinutuximab Brand Names in Pakistan:

No Brands Available in Pakistan.