Included as part of the PRECAUTIONS section.
Serious Infusion Reactions
Serious infusion reactions requiring urgent intervention
including blood pressure support, bronchodilator therapy, corticosteroids,
infusion rate reduction, infusion interruption, or permanent discontinuation of
Unituxin included facial and upper airway edema, dyspnea, bronchospasm,
stridor, urticaria, and hypotension. Infusion reactions generally occurred
during or within 24 hours of completing the Unituxin infusion. Due to
overlapping signs and symptoms, it was not possible to distinguish between
infusion reactions and hypersensitivity reactions in some cases.
In Study 1, Severe (Grade 3 or 4) infusion reactions
occurred in 35 (26%) patients in the Unituxin/13-cis-retinoic acid (RA) group
compared to 1 (1%) patient receiving RA alone. Severe urticaria occurred in 17
(13%) patients in the Unituxin/RA group but did not occur in the RA group.
Serious adverse reactions consistent with anaphylaxis and resulting in
permanent discontinuation of Unituxin occurred in 2 (1%) patients in the
Unituxin/RA group. Additionally, 1 (0.1%) patient had multiple cardiac arrests
and died within 24 hours after having received Unituxin in Study 2.
Prior to each Unituxin dose, administer required
intravenous hydration and premedication with antihistamines, analgesics, and
antipyretics [see DOSAGE AND ADMINISTRATION]. Monitor patients closely
for signs and symptoms of infusion reactions during and for at least 4 hours
following completion of each Unituxin infusion in a setting where
cardiopulmonary resuscitation medication and equipment are available.
For mild to moderate infusion reactions such as transient
rash, fever, rigors, and localized urticaria that respond promptly to
antihistamines or antipyretics, decrease the Unituxin infusion rate and monitor
closely. Immediately interrupt or permanently discontinue Unituxin and
institute supportive management for severe or prolonged infusion reactions.
Permanently discontinue Unituxin and institute supportive management for
life-threatening infusion reactions [see DOSAGE AND ADMINISTRATION].
In Study 1, 114 (85%) patients treated in the Unituxin/RA
group experienced pain despite pretreatment with analgesics including morphine
sulfate infusion. Severe (Grade 3) pain occurred in 68 (51%) patients in the
Unituxin/RA group compared to 5 (5%) patients in the RA group. Pain typically
occurred during the Unituxin infusion and was most commonly reported as
abdominal pain, generalized pain, extremity pain, back pain, neuralgia,
musculoskeletal chest pain, and arthralgia.
Premedicate with analgesics including intravenous opioids
prior to each dose of Unituxin and continue analgesics until two hours
following completion of Unituxin [see DOSAGE AND ADMINISTRATION].
For severe pain, decrease the Unituxin infusion rate to
0.875 mg/m²/hour. Discontinue Unituxin if pain is not adequately controlled
despite infusion rate reduction and institution of maximum supportive measures [see
DOSAGE AND ADMINISTRATION].
In Study 1, severe (Grade 3) peripheral sensory
neuropathy occurred in 2 (1%) patients and severe peripheral motor neuropathy
occurred in 2 (1%) patients in the Unituxin/RA group. No patients treated with
RA alone experienced severe peripheral neuropathy. The duration and
reversibility of peripheral neuropathy occurring in Study 1 was not documented.
In Study 3, no patients experienced peripheral motor neuropathy. Among the 9
(9%) patients who experienced peripheral sensory neuropathy of any severity,
the median (min, max) duration of peripheral sensory neuropathy was 9 (3, 163)
In a study of a related anti-GD2 antibody conducted in 12
adult patients with metastatic melanoma, 2 (13%) patients developed severe
motor neuropathy. One patient developed lower extremity weakness and inability
to ambulate that persisted for approximately 6 weeks. Another patient developed
severe lower extremity weakness resulting in an inability to ambulate without
assistance that lasted for approximately 16 weeks and neurogenic bladder that
lasted for approximately 3 weeks. Complete resolution of motor neuropathy was
not documented in this case.
Permanently discontinue Unituxin in patients with
peripheral motor neuropathy of Grade 2 or greater severity, Grade 3 sensory
neuropathy that interferes with daily activities for more than 2 weeks, or
Grade 4 sensory neuropathy [see DOSAGE AND ADMINISTRATION].
Neurological Disorders Of The Eye
Neurological disorders of the eye experienced by two or
more patients treated with Unituxin in Studies 1, 2, or 3 included blurred
vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder,
eyelid ptosis, and papilledema.
In Study 1, 3 (2%) patients in the Unituxin/RA group
experienced blurred vision, compared to no patients in the RA group. Diplopia,
mydriasis, and unequal pupillary size occurred in 1 patient each in the
Unituxin/RA group, compared to no patients in the RA group. The duration of eye
disorders occurring in Study 1 was not documented. In Study 3, eye disorders
occurred in 16 (15%) patients, and in 3 (3%) patients resolution of the eye
disorder was not documented. Among the cases with documented resolution, the
median duration of eye disorders was 4 days (range: 0, 221 days).
Interrupt Unituxin 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 Unituxin is
warranted, decrease the Unituxin dose by 50%. Permanently discontinue Unituxin
in patients with recurrent signs or symptoms of an eye disorder following dose
reduction and in patients who experience loss of vision [see DOSAGE AND
Prolonged Urinary Retention
Urinary retention that persists for weeks to months
following discontinuation of opioids has occurred in patients treated with
Unituxin. Permanently discontinue Unituxin in patients with urinary retention
that does not resolve following discontinuation of opioids [see DOSAGE AND
ADMINISTRATION and Postmarketing Experience].
Transverse myelitis has occurred in patients treated with
Unituxin. Promptly evaluate any patient with signs or symptoms of transverse myelitis such as weakness, paresthesia, sensory loss, or incontinence.
Permanently discontinue Unituxin in patients who develop transverse myelitis [see
DOSAGE AND ADMINISTRATION and Postmarketing Experience].
Reversible Posterior Leukoencephalopathy Syndrome
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
has occurred in patients treated with Unituxin. Institute appropriate medical
treatment and permanently discontinue Unituxin in patients with signs and
symptoms of RPLS (e.g., severe headache, hypertension, visual changes,
lethargy, or seizures) [see DOSAGE AND ADMINISTRATION and Postmarketing
Capillary Leak Syndrome
In Study 1, severe (Grade 3 to 5) capillary leak syndrome
occurred in 31 (23%) patients in the Unituxin/RA group and in no patients
treated with RA alone. Additionally, capillary leak syndrome was reported as a
serious adverse reaction in 9 (6%) patients in the Unituxin/RA group and in no
patients treated with RA alone. Immediately interrupt or discontinue Unituxin
and institute supportive management in patients with symptomatic or severe
capillary leak syndrome [see DOSAGE AND ADMINISTRATION].
In Study 1, severe (Grade 3 or 4) hypotension occurred in
22 (16%) patients in the Unituxin/RA group compared to no patients in the RA
Prior to each Unituxin infusion, administer required intravenous
hydration. Closely monitor blood pressure during Unituxin treatment.
Immediately interrupt or discontinue Unituxin and institute supportive
management in patients with symptomatic hypotension, systolic blood pressure
(SBP) less than lower limit of normal for age, or SBP that is decreased by more
than 15% compared to baseline [see DOSAGE AND ADMINISTRATION].
In Study 1, severe (Grade 3 or 4) bacteremia requiring
intravenous antibiotics or other urgent intervention occurred in 17 (13%)
patients in the Unituxin/RA group compared to 5 (5%) patients treated with RA
alone. Sepsis occurred in 24 (18%) patients in the Unituxin/RA group and in 10
(9%) patients in the RA group.
Monitor patients closely for signs and symptoms of systemic
infection and temporarily discontinue Unituxin in patients who develop systemic
infection until resolution of the infection [see DOSAGE AND ADMINISTRATION].
Bone Marrow Suppression
In Study 1, severe (Grade 3 or 4) thrombocytopenia (39%
vs. 25%), anemia (34% vs. 16%), neutropenia (34% vs. 13%), and febrile
neutropenia (4% vs. 0 patients) occurred more commonly in patients in the
Unituxin/RA group compared to patients treated with RA alone. Monitor
peripheral blood counts closely during therapy with Unituxin.
Electrolyte abnormalities occurring in at least 25% of
patients who received Unituxin/RA in Study 1 included hyponatremia,
hypokalemia, and hypocalcemia. Severe (Grade 3 or 4) hypokalemia and hyponatremia
occurred in 37% and 23% of patients in the Unituxin/RA group respectively
compared to 2% and 4% of patients in the RA group. In a study of a related
antiGD2 antibody conducted in 12 adult patients with metastatic melanoma, 2
(13%) patients developed syndrome of inappropriate antidiuretic hormone
secretion resulting in severe hyponatremia. Monitor serum electrolytes daily
during therapy with Unituxin.
Atypical Hemolytic Uremic Syndrome
Hemolytic uremic syndrome in the absence of documented
infection and resulting in renal insufficiency, electrolyte abnormalities,
anemia, and hypertension occurred in two patients enrolled in Study 2 following
receipt of the first cycle of dinutuximab. Atypical hemolytic uremic syndrome recurred
following rechallenge with Unituxin in one patient. Permanently discontinue
Unituxin and institute supportive management for signs of hemolytic uremic
Based on its mechanism of action, Unituxin may cause
fetal harm when administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential to use
effective contraception during treatment, and for two months after the last
dose of Unituxin [see Use in Specific Populations and CLINICAL
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No animal studies have been conducted to evaluate the
carcinogenic or mutagenic potential of dinutuximab.
Dedicated studies examining the effects of dinutuximab on
fertility in animals have not been conducted. No clear effects on reproductive
organs were observed in general toxicology studies conducted in rats.
Use In Specific Populations
Based on its mechanism of action, Unituxin may cause
fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY].
There are no studies in pregnant women and no reproductive studies in animals
to inform the drug-associated risk. Monoclonal antibodies are transported
across the placenta in a linear fashion as pregnancy progresses, with the
largest amount transferred during the third trimester. Advise pregnant women of
the potential risk to a fetus. The background risk of major birth defects and
miscarriage for the indicated population is unknown. However, the background
risk in the U.S. general population of major birth defects is 2-4% and of
miscarriage is 15-20% of clinically recognized pregnancies.
There is no information available on the presence of
dinutuximab in human milk, the effects of the drug on the breastfed infant, or
the effects of the drug on milk production. However, human IgG is present in
human milk. Because of the potential for serious adverse reactions in a
breastfed infant, advise a nursing woman to discontinue breastfeeding during
treatment with Unituxin.
Females and Males of Reproductive Potential
Unituxin may cause fetal harm [see Use in Specific
Populations]. Advise females of reproductive potential to use effective
contraception during treatment and for two months after the last dose of
The safety and effectiveness of Unituxin as part of multi-agent,
multimodality therapy have been established in pediatric patients with
high-risk neuroblastoma based on results of an open-label, randomized (1:1)
trial conducted in 226 patients aged 11 months to 15 years (median age 3.8
years) (Study 1). Prior to enrollment, patients achieved at least a partial
response to prior first-line therapy for high-risk neuroblastoma consisting of
induction combination chemotherapy, maximum feasible surgical resection,
myeloablative consolidation chemotherapy followed by autologous stem cell
transplant, and received radiation therapy to residual soft tissue disease.
Patients randomized to the Unituxin/13-cis-retinoic acid (RA) arm (Unituxin/RA)
received up to five cycles of Unituxin in combination with alternating cycles
of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2
(IL-2) plus RA, followed by one cycle of RA alone. Patients randomized to the
RA arm received up to six cycles of RA monotherapy. Study 1 demonstrated an
improvement in event-free survival and overall survival in patients in the
Unituxin/RA arm compared to those in the RA arm [see ADVERSE REACTIONS, CLINICAL
PHARMACOLOGY, and Clinical Studies].
The safety and effectiveness of Unituxin in geriatric
patients have not been established.
Unituxin has not been studied in patients with renal
Unituxin has not been studied in patients with hepatic