Unituxin
Generic
Name: dinutuximab
Dosage Form: injection
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).
Indications and Usage for Unituxin
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)].
Unituxin 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)].
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
|
|
|
|
|
|
|
|
|
|
|
|
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.
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.
|
Instructions
for Preparation and Administration
Preparation
·
Store vials in a refrigerator
at 2°C to 8°C (36°F to 46°F). Protect from light by storing in the outer
carton. DO NOT FREEZE OR SHAKE vials.
·
Inspect visually for
particulate matter and discoloration prior to administration. Do not administer
Unituxin and discard the single-use vial if the solution is cloudy, has
pronounced discoloration, or contains particulate matter.
·
Aseptically withdraw the
required volume of Unituxin from the single-use vial and inject into a 100 mL
bag of 0.9% Sodium Chloride Injection, USP. Mix by gentle inversion. Do not
shake. Discard unused contents of the vial.
·
Store the diluted Unituxin
solution under refrigeration (2°C to 8°C). Initiate infusion within 4 hours of
preparation.
·
Discard diluted Unituxin
solution 24 hours after preparation.
Administration
·
Administer Unituxin as a
diluted intravenous infusion only [see Dosage
and Administration (2.1)]. Do not
administer Unituxin as an intravenous push or bolus.
Dosage Forms and Strengths
Injection: 17.5 mg/5 mL (3.5
mg/mL) solution in a single-use vial.
Contraindications
Unituxin is contraindicated in
patients with a history of anaphylaxis to dinutuximab.
Warnings and PrecautionsSerious
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 (2.2)]. 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 (2.3)].
Neurotoxicity
Pain
In Study 1, 114 (85%) patients
treated in the Unituxin/RA group experienced pain despite pre-treatment 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 (2.2)].
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 (2.3)].
Peripheral Neuropathy
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) days.
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 (2.3)].
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 Administration (2.3)].
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 (2.3) and Postmarketing
Experience (6.3)].
Transverse Myelitis
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 (2.3) and Postmarketing
Experience (6.3)].
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 (2.3) and Postmarketing
Experience (6.3)].
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 (2.3)].
Hypotension
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 group.
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 (2.2, 2.3)].
Infection
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 (2.3)].
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
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 anti-GD2 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 syndrome.
Embryo-Fetal
Toxicity
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 (8.1, 8.3) and Clinical Pharmacology
(12.1)].
Adverse Reactions
The following adverse
reactions are discussed in greater detail in other sections of the labeling:
·
Serious Infusion
Reactions [see Boxed
Warning and Warnings
and Precautions (5.1)]
·
Neurotoxicity, including Pain,
Peripheral Neuropathy, Neurological Disorders of the Eye, Prolonged Urinary
Retention, Transverse Myelitis, and Reversible Posterior Leukoencephalopathy
Syndrome [see Boxed
Warning and Warnings
and Precautions (5.2)]
·
Capillary Leak Syndrome [see Warnings and
Precautions (5.3)]
·
Hypotension [see Warnings and
Precautions (5.4)]
·
Infection [see Warnings and
Precautions (5.5)]
·
Bone Marrow Suppression [see Warnings and Precautions
(5.6)]
·
Electrolyte
Abnormalities [see Warnings
and Precautions (5.7)]
·
Atypical Hemolytic Uremic
Syndrome [see Warnings
and Precautions (5.8)]
·
Embryo-Fetal Toxicity [see Warnings and
Precautions (5.9)]
Clinical
Trials Experience
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect rates observed in clinical
practice.
The data described below
reflect exposure to Unituxin at the recommended dose and schedule in 1021
patients with high-risk neuroblastoma enrolled in an open label, randomized
(Study 1) or single arm clinical trials (Study 2 and Study 3). Prior to
enrollment, patients received therapy consisting of induction combination
chemotherapy, maximum feasible surgical resection, myeloablative consolidation
chemotherapy followed by autologous stem cell transplant, and radiation therapy
to residual soft tissue disease. Patients received Unituxin in combination with
granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2)
and 13-cis-retinoic acid (RA). Treatment commenced within 95 days post
autologous stem cell transplant in Study 1, within 210 days of autologous stem
cell transplant in Study 2, and within 110 days of autologous stem cell
transplant in Study 3.
Study 1
In a randomized, open label,
multi-center study (Study 1), 134 patients received dinutuximab in combination
with GM-CSF, IL-2 and RA (Unituxin/RA group), including 109 randomized patients
and 25 patients with biopsy-proven residual disease who were non-randomly
assigned to receive dinutuximab. A total of 106 randomized patients received RA
alone (RA group) [see Dosage
and Administration (2)and Clinical Studies (14)]. Patients had a median age at
enrollment of 3.8 years (range: 0.94 to 15.3 years), and were predominantly
male (60%) and White (82%). In Study 1, adverse reactions of Grade 3 or greater
severity were comprehensively collected, but adverse reactions of Grade 1 or 2
severity were collected sporadically and laboratory data were not
comprehensively collected.
Approximately 71% of patients
in the Unituxin/RA group and 77% of patients in the RA group completed planned
treatment. The most common reason for premature discontinuation of study
therapy was adverse reactions in the Unituxin/RA group (19%) and progressive
disease (17%) in the RA group.
The most common adverse drug
reactions (≥ 25%) in the Unituxin/RA group were pain, pyrexia,
thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia,
increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia,
capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased
aspartate aminotransferase, and hypocalcemia. The most common serious adverse
reactions (≥ 5%) in the Unituxin/RA group were infections, infusion reactions,
hypokalemia, hypotension, pain, fever, and capillary leak syndrome.
Table 5 lists the adverse
reactions reported in at least 10% of patients in the Unituxin/RA group for
which there was a between group difference of at least 5% (all grades) or 2%
(Grade 3 or greater severity).
Table 5: Selected Adverse Reactions Occurring in at Least 10% of
Patients in the Unituxin/RA Group in Study 1
|
|
|
Adverse Reaction*,†
|
Unituxin/RA
(N=134)
|
RA
(N=106)
|
|
|
All Grades
(%)
|
Grades 3-4
(%)
|
All Grades
(%)
|
Grades 3-4
(%)
|
|
|
*
Includes adverse
reactions that occurred in at least 10% of patients in the Unituxin/RA group
with at least a 5% (All Grades) or 2% (Grades 3-5) absolute higher incidence
in the Unituxin/RA group compared to the RA group.
†
Adverse drug
reactions were graded using CTCAE version 3.0.
‡
Includes
preferred terms abdominal pain, abdominal pain upper, arthralgia, back pain,
bladder pain, bone pain, chest pain, facial pain, gingival pain, infusion
related reaction, musculoskeletal chest pain, myalgia, neck pain, neuralgia,
oropharyngeal pain, pain, pain in extremity, and proctalgia.
§
Based on investigator
reported adverse reactions.
¶
One Grade 5
adverse reaction.
#
Includes
preferred terms gastrointestinal hemorrhage, hematochezia, rectal hemorrhage,
hematemesis, upper gastrointestinal hemorrhage, hematuria, hemorrhage urinary
tract, renal hemorrhage, epistaxis, respiratory tract hemorrhage,
disseminated intravascular coagulation, catheter site hemorrhage, hemorrhage
and hematoma.
Þ
Includes preferred terms tachycardia and sinus
tachycardia.
|
|
|
General Disorders and Administration Site Conditions
|
|
|
Pain‡
|
85
|
51
|
16
|
6
|
|
|
Pyrexia
|
72
|
40
|
27
|
6
|
|
|
Edema
|
17
|
0
|
0
|
0
|
|
|
Blood and Lymphatic System Disorders§
|
|
|
Thrombocytopenia
|
66
|
39
|
43
|
25
|
|
|
Lymphopenia§
|
62
|
51
|
36
|
20
|
|
|
Anemia
|
51
|
34
|
22
|
16
|
|
|
Neutropenia
|
39
|
34
|
16
|
13
|
|
|
Immune System Disorders
|
|
|
Infusion
reactions
|
60
|
25
|
9
|
1
|
|
|
Vascular Disorders
|
|
|
Hypotension
|
60
|
16
|
3
|
0
|
|
|
Capillary
leak syndrome¶
|
40
|
23
|
1
|
0
|
|
|
Hemorrhage#
|
17
|
6
|
6
|
3
|
|
|
Hypertension
|
14
|
2
|
7
|
1
|
|
|
Metabolism and Nutrition Disorders
|
|
|
Hyponatremia§
|
58
|
23
|
12
|
4
|
|
|
Hypokalemia§
|
43
|
37
|
4
|
2
|
|
|
Hypoalbuminemia§
|
33
|
7
|
3
|
0
|
|
|
Hypocalcemia§
|
27
|
7
|
0
|
0
|
|
|
Hypophosphatemia§
|
20
|
8
|
3
|
0
|
|
|
Hyperglycemia§
|
18
|
6
|
4
|
1
|
|
|
Hypertriglyceridemia§
|
16
|
1
|
11
|
1
|
|
|
Decreased
appetite
|
15
|
10
|
5
|
4
|
|
|
Hypomagnesemia§
|
12
|
2
|
1
|
0
|
|
|
Investigations
|
|
|
Increased
alanine aminotransferase§
|
56
|
23
|
31
|
3
|
|
|
Increased
aspartate aminotransferase§
|
28
|
10
|
7
|
0
|
|
|
Increased
serum creatinine§
|
15
|
2
|
6
|
0
|
|
|
Increased
weight
|
10
|
0
|
0
|
0
|
|
|
Gastrointestinal Disorders
|
|
|
Vomiting
|
46
|
6
|
19
|
3
|
|
|
Diarrhea
|
43
|
13
|
15
|
1
|
|
|
Nausea
|
10
|
2
|
3
|
1
|
|
|
Skin and Subcutaneous Tissue Disorders
|
|
|
Urticaria
|
37
|
13
|
3
|
0
|
|
|
Respiratory, Thoracic and Mediastinal Disorders
|
|
|
Hypoxia
|
24
|
12
|
2
|
1
|
|
|
Cardiac Disorders
|
|
|
TachycardiaÞ
|
19
|
2
|
1
|
0
|
|
|
Infections and Infestations
|
|
|
Sepsis
|
18
|
16
|
9
|
9
|
|
|
Device
related infection
|
16
|
16
|
11
|
11
|
|
|
Renal and Urinary Disorders
|
|
|
Proteinuria§
|
16
|
0
|
3
|
1
|
|
|
Nervous System Disorders
|
|
|
Peripheral
neuropathy
|
13
|
3
|
6
|
0
|
|
Table 6 compares the
per-patient incidence of selected adverse reactions occurring during cycles
containing dinutuximab in combination with GM-CSF (Cycles 1, 3, and 5) with
cycles containing dinutuximab in combination with IL-2 (Cycles 2 and 4).
Table 6: Comparison of Adverse Events by Treatment Cycle in the
Unituxin/RA Group in Study 1
|
|
|
Preferred Term*,†
|
All Grades
|
Severe
|
|
|
GM-CSF
N=134
(%)
|
IL-2‡
N=127
(%)
|
GM-CSF
N=134
(%)
|
IL-2‡
N=127
(%)
|
|
|
Abbreviations: GM-CSF:
granulocyte-macrophage colony-stimulating factor; IL-2: interleukin-2.
|
|
|
*
Includes
preferred terms with a per-patient incidence of at least 20% in the Unituxin
and RA group for either IL-2 or GM-CSF containing cycles.
†
Adverse drug
reactions were graded using CTCAE version 3.0.
‡
Seven patients
who received GM-CSF in Cycle 1 discontinued prior to starting Cycle 2.
§
Includes
preferred terms abdominal pain, abdominal pain upper, arthralgia, back pain,
bladder pain, bone pain, chest pain, facial pain, gingival pain, infusion
related reaction, musculoskeletal chest pain, myalgia, neck pain, neuralgia,
oropharyngeal pain, pain, pain in extremity, and proctalgia.
¶
Based on investigator reported adverse reactions.
|
|
|
General Disorders and administration site conditions
|
|
|
Pyrexia
|
55
|
65
|
10
|
37
|
|
|
Pain§
|
77
|
61
|
43
|
35
|
|
|
Blood and Lymphatic System Disorders¶
|
|
|
Thrombocytopenia
|
62
|
61
|
31
|
33
|
|
|
Lymphopenia
|
54
|
61
|
33
|
50
|
|
|
Anemia
|
42
|
42
|
21
|
24
|
|
|
Neutropenia
|
25
|
32
|
19
|
28
|
|
|
Immune System Disorders
|
|
|
Infusion
reactions
|
47
|
54
|
10
|
20
|
|
|
Vascular Disorders
|
|
|
Hypotension
|
43
|
54
|
5
|
16
|
|
|
Capillary
leak syndrome
|
22
|
36
|
11
|
20
|
|
|
Metabolism and Nutrition Disorders¶
|
|
|
Hyponatremia
|
36
|
55
|
5
|
21
|
|
|
Hypokalemia
|
26
|
39
|
13
|
33
|
|
|
Hypoalbuminemia
|
29
|
29
|
3
|
5
|
|
|
Hypocalcemia
|
20
|
21
|
2
|
6
|
|
|
Investigations¶
|
|
|
Increased
alanine aminotransferase
|
43
|
48
|
15
|
13
|
|
|
Aspartate
aminotransferase increased
|
16
|
21
|
4
|
7
|
|
|
Gastrointestinal Disorders
|
|
|
Diarrhea
|
31
|
37
|
6
|
13
|
|
|
Vomiting
|
33
|
35
|
3
|
2
|
|
|
Skin and Subcutaneous Tissue Disorders
|
|
|
Urticaria
|
25
|
29
|
7
|
7
|
|
Study 2 and Study 3
Study 2 was a single arm,
multicenter expanded access trial that enrolled patients with high-risk
neuroblastoma (N=783). The reported adverse event profile of dinutuximab in
Study 2 was similar to that observed in Study 1.
Study 3 was a multicenter,
single arm safety study of dinutuximab in combination with GM-CSF, IL-2 and RA.
In Study 3, adverse events of all CTCAE grades and laboratory data were
systematically and comprehensively collected. Of 104 patients enrolled and
treated in Study 3, 77% of patients completed study therapy. In general, the
adverse reaction profile of dinutuximab observed in Study 3 was similar to that
observed in Study 1 and Study 2. The following adverse reactions not previously
reported in Study 1 were reported in at least 10% of patients in Study 3: nasal
congestion (20%) and wheezing (15%). Table 7 provides the per-patient incidence
of laboratory abnormalities in Study 3.
Table 7: Per-Patient Incidence of Selected (≥ 5% Grade 3-4)
Laboratory Abnormalities in Study 3
|
|
|
Laboratory Test*
|
Grade†
|
|
|
All Grades %
|
Grades 3-4 %
|
|
|
ND: not
determined
|
|
|
*
Laboratory
abnormalities with a per-patient incidence of at least 20% (all grades) and
at least a 5% per-patient incidence of severe (Grade 3 or 4) laboratory
abnormalities.
†
Based on CTCAE
version 4.0.
‡
Urinalysis results were reported as positive or
negative without assessment of grade.
|
|
|
Hematology
|
|
|
Anemia
|
100
|
46
|
|
|
Neutropenia
|
99
|
63
|
|
|
Thrombocytopenia
|
98
|
49
|
|
|
Chemistry
|
|
|
Hypoalbuminemia
|
100
|
8
|
|
|
Hypocalcemia
|
97
|
7
|
|
|
Hyponatremia
|
93
|
36
|
|
|
Hyperglycemia
|
87
|
6
|
|
|
Aspartate
Aminotransferase Increased
|
84
|
8
|
|
|
Alanine
Aminotransferase Increased
|
83
|
13
|
|
|
Hypokalemia
|
82
|
41
|
|
|
Hypophosphatemia
|
78
|
6
|
|
|
Urinalysis‡
|
|
|
Urine
protein
|
66
|
ND
|
|
|
Red
blood cell casts
|
38
|
ND
|
|
Immunogenicity
As with all therapeutic
proteins, patients treated with Unituxin may develop anti-drug antibodies. In
clinical studies, 52 of 284 (18%) patients from Study 2 and 13 of 103 (13%)
patients from Study 3 tested positive for anti-dinutuximab binding antibodies.
Neutralizing antibodies were detected in 3.6% of patients who were tested for
anti-dinutuximab binding antibodies in Study 2 and Study 3. However, due to the
limitations of the assay, the incidence of neutralizing antibodies may not have
been reliably determined.
The detection of antibody
formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody (including neutralizing
antibody) positivity in an assay may be influenced by several factors including
assay methodology, sample handling, timing of sample collection, concomitant
medications, and underlying disease. For these reasons, comparison of incidence
of antibodies to Unituxin with the incidences of antibodies to other products
may be misleading.
Postmarketing
Experience
The following adverse
reactions have been identified during post-approval use of Unituxin. Because
these reactions are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
·
Neurotoxicity: prolonged
urinary retention, transverse myelitis, and reversible posterior
leukoencephalopathy syndrome (RPLS) [see Warnings
and Precautions (5.2)].
Drug Interactions
No drug-drug interaction
studies have been conducted with dinutuximab.
USE IN SPECIFIC POPULATIONSPregnancy
Risk Summary
Based on its mechanism of
action, Unituxin may cause fetal harm when administered to a pregnant
woman [see Clinical Pharmacology
(12.1)]. 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.
Lactation
Risk Summary
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
Contraception
Females
Unituxin may cause fetal
harm [see Use in Specific
Populations (8.1)]. Advise females of reproductive potential to use effective
contraception during treatment and for two months after the last dose of
Unituxin.
Pediatric Use
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 (6), Clinical Pharmacology
(12),
and Clinical Studies (14)].
Geriatric Use
The safety and effectiveness
of Unituxin in geriatric patients have not been established.
Renal
Impairment
Unituxin has not been studied
in patients with renal impairment.
Hepatic
Impairment
Unituxin has not been studied
in patients with hepatic impairment.
Unituxin Description
Unituxin (dinutuximab) is a
chimeric monoclonal antibody composed of murine variable heavy and light chain
regions and the human constant region for the heavy chain IgG1 and light chain
kappa. Unituxin binds to the glycolipid disialoganglioside (GD2). Dinutuximab
is produced in the murine myeloma cell line, SP2/0.
Unituxin is a sterile,
preservative-free, clear/colorless to slightly opalescent solution for
intravenous infusion. Unituxin is supplied in single-use vials of 17.5 mg/5 mL.
Each vial contains 3.5 mg/mL of dinutuximab, histidine (20 mM), polysorbate 20
(0.05%), sodium chloride (150 mM), and water for injection; hydrochloric acid
is added to adjust pH to 6.8.
Unituxin - Clinical PharmacologyMechanism of
Action
Dinutuximab binds to the
glycolipid GD2. This glycolipid is expressed on neuroblastoma cells and on
normal cells of neuroectodermal origin, including the central nervous system
and peripheral nerves. Dinutuximab binds to cell surface GD2 and induces cell
lysis of GD2-expressing cells through antibody-dependent cell-mediated
cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Pharmacokinetics
The pharmacokinetics of
dinutuximab was evaluated by a population pharmacokinetic analysis in a
clinical study of Unituxin in combination with GM-CSF, IL-2, and RA. In this
study, 27 children with high-risk neuroblastoma (age: 3.9±1.9 years) received
up to 5 cycles of Unituxin at 17.5 mg/m2/day as an intravenous infusion over 10 to 20 hours for 4
consecutive days every 28 days. The observed maximum plasma dinutuximab
concentration (Cmax) was 11.5 mcg/mL [20%, coefficient of variation (CV)]. The mean
volume of distribution at steady state (Vdss) was 5.4 L (28%). The
clearance was 0.21 L/day (62%) and increased with body size. The terminal
half-life was 10 days (56%).
No formal pharmacokinetic
studies were conducted in patients with renal or hepatic impairment.
Nonclinical ToxicologyCarcinogenesis,
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.
Animal
Toxicology and/or Pharmacology
Non-clinical studies suggest
that dinutuximab-induced neuropathic pain is mediated by binding of the
antibody to the GD2 antigen located on the surface of peripheral nerve fibers
and myelin and subsequent induction of CDC and ADCC activity.
Clinical Studies
The safety and effectiveness
of Unituxin was evaluated in a randomized, open-label, multicenter trial
conducted in pediatric patients with high-risk neuroblastoma (Study 1). All
patients had received prior therapy consisting of induction combination
chemotherapy, maximum feasible surgical resection, myeloablative consolidation
chemotherapy followed by autologous stem cell transplant, and radiation therapy
to residual soft tissue disease. Patients were randomized between Day 50 and
Day 77 post-autologous stem cell transplantation.
Patients were required to have
achieved at least a partial response prior to autologous stem cell
transplantation, have no evidence of disease progression following completion
of front-line multi-modality therapy, have adequate pulmonary function (no
dyspnea at rest and peripheral arterial oxygen saturation of at least 94% on
room air), adequate hepatic function (total bilirubin < 1.5 × the upper
limit of normal and ALT < 5 × the upper limit of normal), adequate cardiac
function (shortening fraction of > 30% by echocardiogram, or if shortening
fraction abnormal, ejection fraction of 55% by gated radionuclide study), and
adequate renal function (glomerular filtration rate at least 70 mL/min/1.73 m2). Patients with systemic
infections or a requirement for concomitant systemic corticosteroids or
immunosuppressant usage were not eligible for enrollment.
Patients randomized to the
Unituxin/RA arm received up to five cycles of dinutuximab (clinical trials
material) in combination with granulocyte-macrophage colony-stimulating factor
(GM-CSF) (Table 8) or interleukin-2 (IL-2) (Table 9) plus 13-cis-retinoic acid
(RA), followed by one cycle of RA alone. Patients randomized to the RA arm received
six cycles of RA. Dinutuximab was administered at a dose of 17.5 mg/m2/day (equivalent to 25 mg/m2/day of clinical trials
material) on four consecutive days. Patients in both treatment arms received
six cycles of RA at a dose of 160 mg/m2/day orally (for patients weighing more than 12 kg) or 5.33
mg/kg/day (for patients weighing less than or equal to 12 kg) in two divided
doses for 14 consecutive days.
A total of 226 patients were
randomized, 113 patients to each arm. In general, demographic and baseline
tumor characteristics were similar across study arms. Across the study
population, 60% were male, the median age was 3.8 years and 3% of patients were
less than 1.5 years, 82% were White and 7% were Black. The majority (80%) of
patients had International Neuroblastoma Staging System Stage 4 disease.
Thirty-five percent of patients had a complete response, 43% had a very good
partial response, and 23% had a partial response to therapy received prior to
autologous stem cell transplant. Forty-six percent of patients had
neuroblastoma that was not MYCN-amplified, 36% had tumors with known
MYCN-amplification, and MYCN status was unknown or missing in 19% of patients.
Forty-three percent of patients had hyperdiploid tumors, 36% had diploid
tumors, and DNA ploidy status was unknown or missing in 21% of patients.
The major efficacy outcome
measure was investigator-assessed event-free survival (EFS), defined as the
time from randomization to the first occurrence of relapse, progressive
disease, secondary malignancy, or death. Overall survival (OS) was also
evaluated. After observing a numerical improvement in EFS based on the seventh
interim analysis, the Data Monitoring Committee recommended termination of
accrual. Efficacy results are shown in Table 10.
Table 10: Efficacy Results
|
|
Efficacy Parameter
|
Unituxin/ RA arm
n=113
|
RA arm
n=113
|
|
NR = not reached
|
|
*
Compared to the
allocated alpha of 0.01 pre-specified for the seventh interim analysis of EFS
†
Based on an additional three years of follow up after
the seventh interim analysis of EFS
|
|
EFS
|
No. of Events
(%)
|
33 (29%)
|
50 (44%)
|
|
Median (95% CI) (years)
|
NR (3.4, NR)
|
1.9 (1.3, NR)
|
|
Hazard
Ratio (95% CI)
|
0.57 (0.37, 0.89)
|
|
p-value
(log-rank test)*
|
0.01
|
|
OS†
|
No. of Events
(%)
|
31 (27%)
|
48 (42%)
|
|
Median (95% CI)
(years)
|
NR (7.5, NR)
|
NR (3.9, NR)
|
|
Hazard
Ratio (95% CI)
|
0.58 (0.37, 0.91)
|
The Kaplan-Meier curve of EFS
is shown in Figure 1.
Figure
1: Kaplan-Meier Curve of Event-Free Survival
HOW SUPPLIED / STORAGE AND HANDLING
Unituxin is supplied in a
carton containing one 17.5 mg/5 mL (3.5 mg/mL) single-use vial.
NDC 66302-014-01
Store Unituxin vials under
refrigeration at 2°C to 8°C until time of use. Do not freeze or shake the vial.
Keep the vial in the outer carton in order to protect from light.
Patient Counseling Information
· Serious
Infusion Reactions
Inform patients and caregivers of the risk of serious infusion reactions and
anaphylaxis and to immediately report any signs or symptoms, such as facial or
lip swelling, urticaria, difficulty breathing, lightheadedness or dizziness
that occur during or within 24 hours following the infusion [see Warnings and
Precautions (5.1)].
· Pain,
Peripheral Neuropathy, Prolonged Urinary Retention, and Transverse Myelitis
Inform patients and caregivers of the risk of severe pain, sensory and motor
neuropathy, prolonged urinary retention, and transverse myelitis, and to
promptly report severe or worsening pain and signs and symptoms such as
numbness, tingling, burning, weakness, or inability to urinate [see Warnings and
Precautions (5.2)].
· Neurological
Disorders of the Eye
Inform patients and caregivers of 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 [see Warnings
and Precautions (5.2)].
· Reversible
Posterior Leukoencephalopathy Syndrome (RPLS)
Inform patients and caregivers of the risk of RPLS and to immediately report
signs or symptoms such as severe headache, hypertension, visual changes,
lethargy, or seizures [see Warnings
and Precautions (5.2)].
· Capillary
Leak Syndrome
Inform patients and caregivers of the risk of capillary leak syndrome and to
immediately report any signs or symptoms [see Warnings
and Precautions (5.3)].
· Hypotension
Inform patients and caregivers of the risk of hypotension during the infusion
and to immediately report any signs or symptoms [see Warnings
and Precautions (5.4)].
· Infection
Inform patients and caregivers of the risk of infection following treatment and
to immediately report any signs or symptoms [see Warnings
and Precautions (5.5)].
· Bone
Marrow Suppression
Inform patients and caregivers of the risk of bone marrow suppression, and to
promptly report signs or symptoms of anemia, thrombocytopenia, or
infection [see Warnings
and Precautions (5.6)].
· Electrolyte
Abnormalities
Inform patients and caregivers of 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 [see Warnings and
Precautions (5.7)].
· Atypical
Hemolytic Uremic Syndrome
Inform patients and caregivers of 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 [see Warnings
and Precautions (5.8)].
· Embryo-Fetal
Toxicity
Advise women of reproductive potential of the potential risk to the fetus if
administered during pregnancy and the need for use of effective contraception
during and for at least two months after completing therapy [see Warnings and
Precautions (5.9)].
©Copyright 2017 United Therapeutics Corp. All rights reserved.
Unituxin manufactured by:
United Therapeutics Corp.
Silver Spring, MD 20910
US License No. 1993
PRINCIPAL DISPLAY PANEL - 5 mL Single Use Vial Box
NDC 66302-014-01
Unituxin™
(dinutuximab)
Injection
17.5
mg/5 mL
(3.5 mg/mL)
For Intravenous Infusion Only
Dilute Prior to Administration
Single Use Vial
Discard Unused Portion
Rx
Only
|
Unituxin dinutuximab injection
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:66302-014
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
DINUTUXIMAB (DINUTUXIMAB)
|
DINUTUXIMAB
|
3.5 mg
in 1 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
histidine
|
|
|
polysorbate 20
|
|
|
sodium chloride
|
|
|
water
|
|
|
hydrochloric acid
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:66302-014-01
|
1 VIAL,
SINGLE-USE in 1 BOX
|
|
|
1
|
|
5 mL in 1 VIAL,
SINGLE-USE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
BLA
|
BLA125516
|
03/10/2015
|
|
|
|
Labeler - United Therapeutics Corp. (965460025)
|
Revised:
03/2017
United Therapeutics
Corp.
