Dinutuximab

Dinutuximab may be found in some form under the following brand names:

• Unituxin

You should not receive dinutuximab if you are allergic to it.

To make sure dinutuximab is safe for you, tell your doctor if you have:

• any type of bacterial, fungal, or viral infection;

• an eye disorder or vision problems;

• bone marrow suppression;

• low blood pressure;

• an electrolyte imbalance (such as low levels of potassium, sodium, or calcium in your blood);

• liver or kidney disease; or

• problems with urination.

Do not use dinutuximab if you are pregnant. It could harm the unborn baby. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 2 months after your treatment ends.

It is not known whether dinutuximab passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Contraindications

• History of anaphylaxis to dinutuximab.1

Warnings/Precautions

Warnings

Serious and potentially life-threatening infusion-related reactions (e.g., facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, hypotension requiring urgent intervention, anaphylaxis) reported in 26% of patients;1 2 generally occur during or within 24 hours following completion of the dinutuximab infusion.1 Fatal cardiac arrest occurred in 1 of 783 patients within 24 hours of dinutuximab administration.1

Closely monitor patients for signs of infusion reactions during and for at least 4 hours following dinutuximab infusion in a setting where resuscitation equipment and agents necessary to treat infusion reactions are readily available.1

Administer IV fluids and premedicate with an antihistamine, analgesic, and antipyretic prior to each dinutuximab infusion.1 (See General under Dosage and Administration.)

Initiate appropriate treatment and supportive care for severe, prolonged, or life-threatening infusion-related reactions.1 Reduction of infusion rate, temporary interruption of therapy, or drug discontinuance may be necessary.1 (See Infusion-related Effects under Dosage and Administration.)

Peripheral neuropathy reported;1 2 median duration of peripheral sensory neuropathy is 9 days (range: 3–163 days).1 (See Actions.)

Lower extremity weakness resulting in an inability to ambulate persisted for approximately 6 weeks in one patient receiving a similar anti-GD2 monoclonal antibody for the treatment of metastatic melanoma.1 In another patient, neurogenic bladder lasted approximately 3 weeks and lower extremity weakness resulting in an inability to ambulate without assistance lasted for approximately 16 weeks; complete resolution of peripheral motor neuropathy not documented in this patient.1

Discontinuance of therapy may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Pain despite premedication with analgesics, including IV morphine, reported commonly.1 2 Grade 3 or 4 pain usually develops during dinutuximab administration in cycle 1 and often subsides during subsequent cycles.2 5 Most commonly described as abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal chest pain, and arthralgia.1 2

Premedicate with analgesics, including an IV opiate analgesic; initiate prior to each dinutuximab infusion and continue for 2 hours following completion of infusion.1 (See Pain Management under Dosage and Administration.)

Reduction of infusion rate or discontinuance of therapy may be necessary.1 (See Pain under Dosage and Administration.)

Other Warnings and Precautions

Capillary leak syndrome reported.1 2 5 10 Generally occurs more frequently during cycles containing IL-2.1 2 5 10

Initiate supportive treatment (i.e., respiratory support, albumin replacement therapy)5 if capillary leak syndrome occurs.1 Temporary interruption followed by reduction of infusion rate or discontinuance of therapy may be necessary.1 (See Capillary Leak Syndrome under Dosage and Administration.)

Hypotension reported.1 2

Closely monitor BP during therapy.1 Administer adequate IV fluids immediately before each dinutuximab infusion.1 (See Hydration under Dosage and Administration.)

Initiate supportive treatment if symptomatic hypotension, SBP less than the LLN for age, or reduction in SBP by >15% compared with baseline occurs.1 Temporary interruption of therapy followed by reduction of infusion rate or discontinuance of therapy may be necessary.1 (See Hypotension under Dosage and Administration.)

Serious infections (e.g., bacteremia, sepsis) reported.1

Monitor for signs and symptoms of systemic infection.1 If a systemic infection develops, interrupt dinutuximab therapy until the infection resolves.1

Adverse ocular effects (e.g., blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, papilledema) reported.1 Generally resolves over time;5 in patients with documented resolution, median duration of ocular disorder was 4 days (range: 0–221 days).1

Temporary interruption of therapy followed by dosage reduction or drug discontinuance may be required.1 (See Ocular Effects under Dosage and Administration.)

Severe thrombocytopenia, anemia, neutropenia, and febrile neutropenia reported.1

Closely monitor peripheral blood cell counts during therapy.1

Electrolyte abnormalities (i.e., hyponatremia, hypokalemia, hypocalcemia) reported.1 Severe hyponatremia caused by SIADH occurred in 2 of 12 adults receiving a similar anti-GD2 monoclonal antibody for the treatment of metastatic melanoma.1

Monitor serum electrolytes daily during therapy.1 Discontinuance of therapy may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Hemolytic uremic syndrome occurring in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension reported in 2 patients, approximately 4 days following cycle 1, in an expanded access study.1 10 Hemolytic uremic syndrome recurred following reinitiation of the drug in one patient.1

If hemolytic uremic syndrome occurs, discontinue dinutuximab therapy and initiate appropriate treatment.1

May cause fetal harm.1 Fetal exposure to dinutuximab may be greater during the third trimester of pregnancy.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use an effective contraceptive method while receiving the drug and for ≥2 months after the drug is discontinued.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Antibodies to dinutuximab, including neutralizing antibodies to the drug, reported.1

Specific Populations

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether dinutuximab is distributed into milk; however, human IgG is distributed into milk.1 Discontinue nursing during therapy and for 6 months after therapy.1 5

Effects of the drug on nursing infants or on human milk production are unknown.1

Safety and efficacy not established in infants <11 months of age.1

Safety and efficacy not established.1

Not studied in patients with hepatic impairment.1

Not studied in patients with renal impairment.1

Common Adverse Effects

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),1 anemia,1 vomiting,1 diarrhea,1 hypokalemia,1 2 capillary leak syndrome,1 neutropenia,1 urticaria,1 hypoalbuminemia,1 hypocalcemia,1 infection.2

• ch14.18
• MOAB Ch14.18

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Unituxin: 17.5 mg/5 mL (5 mL) [contains mouse (murine) and/or hamster protein]

• Antineoplastic Agent, Anti-GD2
• Antineoplastic Agent, Monoclonal Antibody

Neuroblastoma, high-risk: IV: 17.5 mg/m2/day 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).

Premedications:

Analgesics: Administer morphine 50 mcg/kg IV immediately prior to dinutuximab infusion initiation; continue as a morphine drip at an infusion rate of 20 to 50 mcg/kg/hour during and for 2 hours following completion of infusion. May administer additional 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. Consider conversion to fentanyl or hydromorphone if morphine is not tolerated; if pain is inadequately controlled with opioids, consider adjunct therapy with gabapentin or lidocaine.

Antiemetics: Dinutuximab is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

Antihistamine: Administer an antihistamine (eg, diphenhydramine 0.5 to 1 mg/kg/dose; maximum dose 50 mg) IV over 10 to 15 minutes starting 20 minutes prior to dinutuximab infusion and every 4 to 6 hours as tolerated during the infusion.

Antipyretics: Administer acetaminophen (10 to 15 mg/kg/dose; maximum dose 650 mg) 20 minutes prior to each infusion and every 4 to 6 hours as needed for fever and pain. May administer ibuprofen (5 to 10 mg/kg/dose) every 6 hours as needed for control of persistent fever or pain.

IV hydration: Administer NS 10 mL/kg IV over 1 hour just prior to each dinutuximab infusion.

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Must be diluted prior to infusion. Withdraw the required dinutuximab volume and inject into a 100 mL bag of NS. Mix by gentle inversion; do not shake. Discard unused vial contents. Initiate infusion within 4 hours of preparation. Do not use if cloudy, discolored (pronounced), or contains particulates.

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

Dinutuximab 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 dinutuximab 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 dinutuximab and related GD2-binding antibodies, severe motor neuropathy has occurred. Resolution of motor neuropathy did not occur in all cases. Discontinue dinutuximab for severe unresponsive pain, severe sensory neuropathy, and moderate to severe peripheral motor neuropathy.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, lack of appetite, nausea, vomiting, or weight gain. Have patient report immediately to prescriber signs of infusion reaction (chills, dizziness, passing out, fever, itching, angioedema, or difficulty breathing), severe pain, burning or numbness feeling, muscle weakness, difficult urination, urinary incontinence, bowel incontinence, signs of capillary leak syndrome (abnormal heartbeat; angina; shortness of breath; weight gain; vomiting blood or vomit that looks like coffee grounds; black, tarry, or bloody stools; urinary retention or change in amount of urine passed; or hematuria), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of infection, blurred vision, blindness, vision changes, change in pupil size, sensitivity to lights, dizziness, passing out, tachycardia, severe loss of strength and energy, pale skin, edema, signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), or signs of Hemolytic-uremic syndrome (urinary retention; loss of strength and energy; signs of bleeding or bruising; fever; or swelling of the face, hands, feet, or body) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Administration advice:
-Verify that patients have adequate hematologic, respiratory, hepatic, and renal function prior to initiating each course of therapy.
-Administer required premedication and hydration prior to initiation of each course of therapy.

Storage requirements:
-Store vials under refrigeration at 2°C to 8°C until time of use. Do not freeze.
-Do not shake the vial.
-Keep the vial in the outer carton in order to protect from light.

Reconstitution/preparation/techniques:
-Refer to manufacturer product information.

Patient advice:
Patients and caregivers should be informed of these risks:
-The risk of serious infusion reactions and anaphylaxis and to immediately report any signs, such as facial or lip swelling, urticaria, difficulty breathing, lightheadedness, or dizziness that occur during or within 24 hours following the infusion.
-The risk of severe pain and peripheral sensory and motor neuropathy and to promptly report severe or worsening pain and signs of neuropathy such as numbness, tingling, burning, or weakness.
-The risk of capillary leak syndrome and to immediately report any signs or symptoms.
-The risk of hypotension during the infusion and to immediately report any signs or symptoms.
-The risk of infection following treatment and to immediately report any signs or symptoms.
-The risk of neurological disorders of the eye and to promptly report signs or symptoms such as blurred vision, photophobia, ptosis, diplopia, or unequal pupil size.
-The risk of bone marrow suppression, and to promptly report signs or symptoms of anemia, thrombocytopenia, or infection.
-The risk of electrolyte abnormalities including hypokalemia, hyponatremia, and hypocalcemia, and to report any signs or symptoms such as seizures, heart palpitations, and muscle cramping.
-The risk of hemolytic uremic syndrome and to report any signs or symptoms such as fatigue, dizziness, fainting, pallor, edema, decreased urine output, or hematuria.
-The potential risk to the fetus if administered during pregnancy (for women of reproductive potential) and the need for use of effective contraception during and for at least two months after completing therapy.