Unituxin

UNITUXIN- dinutuximab injection
United Therapeutics Corp.

WARNING: SERIOUS INFUSION REACTIONS AND NEUROTOXICITY

Infusion Reactions

  • Serious and potentially life-threatening infusion reactions occurred in 26% of patients treated with Unituxin. Administer required prehydration and premedication including antihistamines prior to each Unituxin infusion. Monitor patients closely for signs and symptoms of an infusion reaction during and for at least four hours following completion of each Unituxin infusion. Immediately interrupt Unituxin for severe infusion reactions and permanently discontinue Unituxin for anaphylaxis (2.2, 2.3, 5.1).

Neurotoxicity

  • Unituxin causes serious neurologic adverse reactions including severe neuropathic pain and peripheral neuropathy.

    Severe neuropathic pain occurs in the majority of patients. Administer intravenous opioid prior to, during, and for 2 hours following completion of the Unituxin infusion.

    In clinical studies of patients with high-risk neuroblastoma, Grade 3 peripheral sensory neuropathy occurred in 2% to 9% of patients. In clinical studies of Unituxin and related GD2-binding antibodies, severe motor neuropathy has occurred. Resolution of motor neuropathy did not occur in all cases. Discontinue Unituxin for severe unresponsive pain, severe sensory neuropathy, and moderate to severe peripheral motor neuropathy (2.2, 2.3, 5.2).

1 INDICATIONS AND USAGE

Unituxin (dinutuximab) is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

  • Verify that patients have adequate hematologic, respiratory, hepatic, and renal function prior to initiating each course of Unituxin [see Clinical Studies (14)].
  • Administer required premedication and hydration prior to initiation of each Unituxin infusion [see Dosage and Administration (2.2)].

2.1 Recommended Dose

  • The recommended dose of Unituxin is 17.5 mg/m2 /day administered as an intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles (Tables 1 and 2 ) [see Dosage and Administration (2.4) and Clinical Studies (14)].
  • Initiate at an infusion rate of 0.875 mg/m2 /hour for 30 minutes. The infusion rate can be gradually increased as tolerated to a maximum rate of 1.75 mg/m2 /hour. Follow dose modification instructions for adverse reactions [see Dosage and Administration (2.3)].
Table 1: Schedule of Unituxin Administration for Cycles 1, 3, and 5
Cycle Day 1 through 3 4 5 6 7 8 through 24*
*
Cycles 1, 3, and 5 are 24 days in duration.
Unituxin X X X X
Table 2: Schedule of Unituxin Administration for Cycles 2 and 4
Cycle Day 1 through 7 8 9 10 11 12 through 32*
*
Cycles 2 and 4 are 32 days in duration.
Unituxin X X X X

2.2 Required Pre-treatment and Guidelines for Pain Management

Intravenous Hydration

  • Administer 0.9% Sodium Chloride Injection, USP 10 mL/kg as an intravenous infusion over one hour just prior to initiating each Unituxin infusion.

Analgesics

  • Administer morphine sulfate (50 mcg/kg) intravenously immediately prior to initiation of Unituxin and then continue as a morphine sulfate drip at an infusion rate of 20 to 50 mcg/kg/hour during and for two hours following completion of Unituxin.
  • Administer additional 25 mcg/kg to 50 mcg/kg intravenous doses of morphine sulfate as needed for pain up to once every 2 hours followed by an increase in the morphine sulfate infusion rate in clinically stable patients.
  • Consider using fentanyl or hydromorphone if morphine sulfate is not tolerated.
  • If pain is inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with intravenous morphine.

Antihistamines and Antipyretics

  • Administer an antihistamine such as diphenhydramine (0.5 to 1 mg/kg; maximum dose 50 mg) intravenously over 10 to 15 minutes starting 20 minutes prior to initiation of Unituxin and as tolerated every 4 to 6 hours during the Unituxin infusion.
  • Administer acetaminophen (10 to 15 mg/kg; maximum dose 650 mg) 20 minutes prior to each Unituxin infusion and every 4 to 6 hours as needed for fever or pain. Administer ibuprofen (5 to 10 mg/kg) every 6 hours as needed for control of persistent fever or pain.

2.3 Dosage Modifications

Manage adverse reactions by infusion interruption, infusion rate reduction, dose reduction, or permanent discontinuation of Unituxin (Table 3 and Table 4) [see Warnings and Precautions (5), Adverse Reactions (6), and Clinical Studies (14)].

Table 3: Adverse Reactions Requiring Permanent Discontinuation of Unituxin
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 or greater peripheral motor neuropathy
Urinary retention that persists following discontinuation of opioids
Transverse myelitis
Reversible posterior leukoencephalopathy syndrome (RPLS)
Subtotal or total vision loss
Grade 4 hyponatremia despite appropriate fluid management
Table 4: Dose Modification for Selected Unituxin Adverse Reactions
*
Symptomatic hypotension, systolic blood pressure (SBP) less than lower limit of normal for age, or SBP decreased by more than 15% compared to baseline.
Infusion-related reactions [see Warnings and Precautions (5.1)]
Mild to moderate adverse reactions such as transient rash, fever, rigors, and localized urticaria that respond promptly to symptomatic treatment
Onset of reaction: Reduce Unituxin infusion rate to 50% of the previous rate and monitor closely.
After resolution: Gradually increase infusion rate up to a maximum rate of 1.75 mg/m2 /hour.
Prolonged or severe adverse reactions such as mild bronchospasm without other symptoms, angioedema that does not affect the airway
Onset of reaction: Immediately interrupt Unituxin.
After resolution: If signs and symptoms resolve rapidly, resume Unituxin at 50% of the previous rate and observe closely.
First recurrence:

Discontinue Unituxin until the following day.

If symptoms resolve and continued treatment is warranted, premedicate with hydrocortisone 1 mg/kg (maximum dose 50 mg) intravenously and administer Unituxin at a rate of 0.875 mg/m2 /hour in an intensive care unit.

Second recurrence: Permanently discontinue Unituxin.
Neurological Disorders of the Eye [see Warnings and Precautions (5.2)]
Onset of reaction: Discontinue Unituxin infusion until resolution.
After resolution: Reduce the Unituxin dose by 50%.
First recurrence or if accompanied by visual impairment: Permanently discontinue Unituxin.
Capillary leak syndrome [see Warnings and Precautions (5.3)]
Moderate to severe but not life-threatening capillary leak syndrome
Onset of reaction: Immediately interrupt Unituxin.
After resolution: Resume Unituxin infusion at 50% of the previous rate.
Life-threatening capillary leak syndrome
Onset of reaction: Discontinue Unituxin for the current cycle.
After resolution: In subsequent cycles, administer Unituxin at 50% of the previous rate.
First recurrence: Permanently discontinue Unituxin.
Hypotension * requiring medical intervention [see Warnings and Precautions (5.4)]
Onset of reaction: Interrupt Unituxin infusion.
After resolution:

Resume Unituxin infusion at 50% of the previous rate.

If blood pressure remains stable for at least 2 hours, increase the infusion rate as tolerated up to a maximum rate of 1.75 mg/m2 /hour.

Severe systemic infection or sepsis [see Warnings and Precautions (5.5)]
Onset of reaction: Discontinue Unituxin until resolution of infection, and then proceed with subsequent cycles of therapy.

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