Portrazza
Generic Name: necitumumab
Dosage Form: injection, solution
WARNING:
CARDIOPULMONARY ARREST and HYPOMAGNESEMIA
· Cardiopulmonary
arrest and/or sudden death occurred in 3.0% of patients treated with Portrazza
in combination with gemcitabine and cisplatin. Closely monitor serum
electrolytes, including serum magnesium, potassium, and calcium, with
aggressive replacement when warranted during and after Portrazza administration [see Warnings and Precautions (5.1, 5.2)].
· Hypomagnesemia
occurred in 83% of patients receiving Portrazza in combination with gemcitabine
and cisplatin, and was severe in 20% of patients. Monitor patients for
hypomagnesemia, hypocalcemia, and hypokalemia prior to each dose of Portrazza
during treatment and for at least 8 weeks following completion of Portrazza.
Withhold Portrazza for Grade 3 or 4 electrolyte abnormalities. Replete
electrolytes as medically appropriate [see Warnings and Precautions (5.2)].
Indications and Usage for PortrazzaSquamous
Non-Small Cell Lung Cancer (NSCLC)
Portrazza™ is indicated, in
combination with gemcitabine and cisplatin, for first-line treatment of
patients with metastatic squamous non-small cell lung cancer.
Limitation of
Use
Portrazza is not indicated for
treatment of non-squamous non-small cell lung cancer [see
Warnings and Precautions (5.6) and Clinical Studies (14.2)].
Portrazza Dosage and AdministrationRecommended
Dose and Schedule
The recommended dose of
Portrazza is 800 mg administered as an intravenous infusion over 60
minutes on Days 1 and 8 of each 3-week cycle prior to gemcitabine and cisplatin
infusion. Continue Portrazza until disease progression or unacceptable
toxicity.
Premedication
·
For patients who have
experienced a previous Grade 1 or 2 infusion-related reaction (IRR),
pre-medicate with diphenhydramine hydrochloride (or equivalent) prior to all
subsequent Portrazza infusions [see Dosage and
Administration (2.3)].
·
For patients who have
experienced a second Grade 1 or 2 occurrence of IRR, pre-medicate for all
subsequent infusions, with diphenhydramine hydrochloride (or equivalent),
acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each
Portrazza infusion [see Dosage and Administration (2.3)].
Dose
Modifications
Infusion-Related Reactions (IRR)
·
Reduce the infusion rate of
Portrazza by 50% for Grade 1 IRR [see Dosage and
Administration (2.2) and Warnings and Precautions (5.5)].
·
Stop the infusion for Grade 2
IRR until signs and symptoms have resolved to Grade 0 or 1; resume Portrazza at
50% reduced rate for all subsequent infusions [see
Dosage and Administration (2.2) and Warnings and Precautions (5.5)].
·
Permanently discontinue
Portrazza for Grade 3 or 4 IRR [see Dosage and
Administration (2.2) and Warnings and Precautions (5.5)].
Dermatologic
Toxicity
·
Withhold Portrazza for Grade 3
rash or acneiform rash until symptoms resolve to Grade ≤2, then resume
Portrazza at reduced dose of 400 mg for at least 1 treatment cycle. If
symptoms do not worsen, may increase dose to 600 mg and 800 mg in
subsequent cycles.
·
Permanently discontinue
Portrazza if:
-
Grade 3 rash or acneiform rash
do not resolve to Grade ≤2 within 6 weeks,
-
Reactions worsen or become intolerable
at a dose of 400 mg
-
Patient experiences Grade 3
skin induration/fibrosis [see Warnings and
Precautions (5.4) and Adverse Reactions (6.1)] or
-
Grade 4 dermatologic
toxicity [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
Preparation
for Administration
Inspect vial contents for
particulate matter and discoloration prior to dilution [see Description (11)]. Discard the vial if
particulate matter or discoloration is identified. Store vials in a
refrigerator at 2° to 8°C (36˚ to 46˚F) until time of use. Keep the vial in the
outer carton in order to protect from light [see
How Supplied/Storage and Handling (16.2)].
·
Dilute the required volume of
Portrazza with 0.9% Sodium Chloride Injection, USP in an intravenous infusion
container to a final volume of 250 mL. Do not use solutions containing
dextrose.
·
Gently invert the container to
ensure adequate mixing.
·
DO NOT FREEZE OR SHAKE the
infusion solution. DO NOT dilute with other solutions or co-infuse with other
electrolytes or medication.
·
Store diluted infusion
solution for no more than 24 hours at 2° to 8°C (36° to 46°F), or no more than
4 hours at room temperature (up to 25°C [77°F]).
·
Discard vial with any unused
portion of Portrazza.
Administration
Visually inspect the diluted
solution for particulate matter and discoloration prior to administration. If
particulate matter or discoloration is identified, discard the solution.
Administer diluted Portrazza
infusion via infusion pump over 60 minutes through a separate infusion line.
Flush the line with 0.9% Sodium Chloride Injection, USP at the end of the
infusion.
Dosage Forms and Strengths
Injection:
800 mg/50 mL (16 mg/mL) solution in a single-dose vial
Contraindications
None
Warnings and PrecautionsCardiopulmonary
Arrest
Cardiopulmonary arrest or
sudden death occurred in 15 (3%) of 538 patients treated with Portrazza plus
gemcitabine and cisplatin as compared to 3 (0.6%) of 541 patients treated with
gemcitabine and cisplatin alone in Study 1. Twelve of the fifteen patients died
within 30 days of the last dose of Portrazza and had comorbid conditions
including history of coronary artery disease (n=3), hypomagnesemia (n=4),
chronic obstructive pulmonary disease (n=7), and hypertension (n=5). Eleven of
the 12 patients had an unwitnessed death. Patients with significant coronary
artery disease, myocardial infarction within 6 months, uncontrolled hypertension,
and uncontrolled congestive heart failure were not enrolled in Study 1. The
incremental risk of cardiopulmonary arrest or sudden death in patients with a
history of coronary artery disease, congestive heart failure, or arrhythmias as
compared to those without these comorbid conditions is not known.
Closely monitor serum
electrolytes, including serum magnesium, potassium, and calcium prior to each
infusion of Portrazza during treatment and after Portrazza administration for
at least 8 weeks after the last dose. Withhold Portrazza for Grade 3 or 4
electrolyte abnormalities; subsequent cycles of Portrazza may be administered
in these patients once electrolyte abnormalities have improved to Grade ≤2.
Replete electrolytes as medically appropriate [see Boxed
Warning and
Warnings and Precautions (5.2)].
Hypomagnesemia
Hypomagnesemia occurred in 83%
of 461/538 patients with available laboratory results treated with Portrazza as
compared to 70% of 457/541 patients with available laboratory results treated
with gemcitabine and cisplatin alone in Study 1. Hypomagnesemia was severe
(Grade 3 or 4) in 20% of the patients treated with Portrazza compared to 7% of
the patients treated with gemcitabine and cisplatin alone. The median time to
development of hypomagnesemia and accompanying electrolyte abnormalities was 6
weeks (25th percentile 4 weeks; 75th percentile 9 weeks)
after initiation of Portrazza. Monitor patients for hypomagnesemia,
hypocalcemia, and hypokalemia prior to each infusion of Portrazza during
treatment and for at least 8 weeks following the completion of Portrazza.
Withhold Portrazza for Grade 3 or 4 electrolyte abnormalities; subsequent
cycles of Portrazza may be administered in these patients once hypomagnesemia
and related electrolyte abnormalities have improved to Grade ≤2. Replete
electrolytes as medically appropriate [see Boxed
Warning,
Warnings and Precautions (5.1), and Adverse
Reactions (6.1)].
Venous and
Arterial Thromboembolic Events
Venous and arterial
thromboembolic events (VTE and ATE), some fatal, were observed with Portrazza
in combination with gemcitabine and cisplatin. In Study 1, the incidence of VTE
was 9% in patients receiving Portrazza plus gemcitabine and cisplatin versus 5%
in patients receiving gemcitabine and cisplatin alone and the incidence of
Grade 3 or higher VTE was 5% versus 3%, respectively. The incidence of fatal
VTEs was similar between arms (0.2% versus 0.2%). The most common VTEs were pulmonary
embolism (5%) and deep-vein thrombosis (2%).
The incidence of ATEs of any
grade was 5% versus 4% and the incidence of Grade 3 or higher ATE was 4% versus
2% in the Portrazza containing and gemcitabine and cisplatin arms,
respectively, in Study 1. The most common ATEs were cerebral stroke and
ischemia (2%) and myocardial infarction (1%).
In an exploratory analysis of
Study 1, the relative risk of VTE or ATE was approximately 3-fold higher in
patients with a reported history of VTE or ATE than in patients with no
reported history of VTE or ATE.
Discontinue Portrazza for
patients with serious or life threatening VTE or ATE.
Dermatologic
Toxicities
Dermatologic toxicities,
including rash, dermatitis acneiform, acne, dry skin, pruritus, generalized
rash, skin fissures, maculo-papular rash and erythema, occurred in 79% of
patients receiving Portrazza in Study 1. Skin toxicity was severe in 8% of
patients. Skin toxicity usually developed within the first 2 weeks of therapy
and resolved within 17 weeks after onset. For Grade 3 skin reactions, modify
the dose of Portrazza [see Dosage and
Administration (2.3) and Adverse Reactions (6.1)]. Limit sun exposure [see Patient Counseling Information (17)].
Discontinue Portrazza for
severe (Grade 4) skin reactions, or for Grade 3 skin induration/fibrosis.
Infusion-Related
Reactions
In Study 1, 1.5% of Portrazza
treated patients experienced IRRs of any severity with 0.4% Grade 3 IRR. No
patients received premedication for IRR for the first dose of Portrazza in
Study 1. Most IRRs occurred after the first or second administration of Portrazza.
Monitor patients during and following Portrazza infusion for signs and symptoms
of IRR. Discontinue Portrazza for serious or life-threatening IRR [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Non-Squamous
NSCLC - Increased Toxicity and Increased Mortality
Portrazza is not indicated for
the treatment of patients with non-squamous NSCLC. In a study of Portrazza plus
pemetrexed and cisplatin (PC) versus PC alone (Study 2), patients treated with
Portrazza and PC experienced more serious (51% versus 41%) and fatal toxicities
(16% versus 10%) and cardiopulmonary arrest/sudden death within 30 days of the
last study drug (3.3% versus 1.3%) compared to patients who received PC
alone [see Clinical Studies (14.2)].
Embryo-Fetal
Toxicity
Based on animal data and its
mechanism of action, Portrazza can cause fetal harm when administered to a
pregnant woman. Disruption or depletion of EGFR in animal models results in
impairment of embryofetal development including effects on placental, lung,
cardiac, skin, and neural development. The absence of EGFR signaling has
resulted in embryolethality as well as post-natal death in animals. Advise
pregnant women of the potential risk to a fetus. Advise females of reproductive
potential to use effective contraception during treatment with Portrazza and
for three months following the final dose [see Use
in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
Adverse Reactions
The following adverse drug
reactions are discussed in greater detail in other sections of the label:
·
Cardiopulmonary Arrest [see Boxed Warning and Warnings and Precautions (5.1)].
·
Hypomagnesemia [see Boxed Warning and Warnings and Precautions (5.2)].
·
Venous and Arterial
Thromboembolic Events [see Warnings and Precautions
(5.3)].
·
Dermatologic Toxicities [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)].
·
Infusion-Related
Reactions [see Dosage and Administration (2.2, 2.3) and Warnings and Precautions (5.5)].
·
Non-Squamous NSCLC - Increased
Toxicity and Increased Mortality [see Warnings and
Precautions (5.6) and Clinical Studies (14.2)].
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 the rates observed in
practice.
The safety of Portrazza was
evaluated in two randomized, open-label trials comparing Portrazza plus
gemcitabine and cisplatin to gemcitabine and cisplatin alone in patients with
squamous NSCLC (Study 1), and Portrazza plus pemetrexed and cisplatin to
pemetrexed and cisplatin alone in patients with non-squamous NSCLC (Study 2).
Since the data in Study 2 demonstrated similar incidence of adverse reactions
over control as observed in Study 1, the safety data from Study 1 alone is
described below.
For patients who received at
least 1 dose of treatment in Study 1, the median age was 62 years (range 32 to
84), 83% were male; 84% were Caucasian; and 92% were smokers. Baseline ECOG
performance status was 0 or 1 for 91%, and 2 for 9% of patients; 90% had
metastatic disease in 2 or more sites. Patients received Portrazza 800 mg
intravenously on days 1 and 8 of each 21 day cycle in combination with up to
six cycles of gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin (75 mg/m2 on day 1). Patients
received Portrazza until progressive disease or unacceptable toxicity.
Patients in the gemcitabine
and cisplatin alone arm received a maximum of 6 cycles, while patients in the
Portrazza plus gemcitabine and cisplatin arm demonstrating at least stable
disease were permitted to continue to receive additional cycles of Portrazza
until disease progression or unacceptable toxicity. The median duration of
exposure to Portrazza in 538 patients who received at least 1 dose of treatment
in Study 1 was 4.6 months (range 0.5 months to 34 months), including 182
patients exposed for at least 6 months and 41 patients exposed for greater than
1 year. Patients were monitored for safety until 30 days after treatment
discontinuation and resolution of treatment-emergent adverse events.
The most common adverse
reactions (all grades) observed in Portrazza-treated patients at a rate of ≥15%
and ≥2% higher than gemcitabine and cisplatin alone were rash (44%), vomiting
(29%), diarrhea (16%), and dermatitis acneiform (15%). The most common severe
(Grade 3 or higher) adverse events that occurred at a ≥2% higher rate in
Portrazza-treated patients compared to patients treated with gemcitabine and
cisplatin alone were venous thromboembolic events (5%; including pulmonary
embolism), rash (4%), and vomiting (3%).
Table 1 contains selected adverse drug reactions observed in Study
1 at an incidence of ≥5% in the Portrazza arm and at ≥2% higher incidence than
the control arm.
Table 1: Adverse Reactions Occurring at
Incidence Rate ≥5% All Grades or a ≥2% Grade 3-4 Difference Between Arms in
Patients Receiving Portrazza in Study 1
|
|
a Pulmonary embolism is also included
in the composite term venous thromboembolic events under system organ class
vascular disorders.
|
|
b VTE is a composite term which
includes: pulmonary embolism, deep vein thrombosis, thrombosis, mesenteric
veins thrombosis, pulmonary artery thrombosis, pulmonary venous thrombosis,
venous thrombosis limb, axillary vein thrombosis, thrombophlebitis, thrombosis
in device, vena cava thrombosis, venous thrombosis, subclavian vein
thrombosis, superior vena cava syndrome, and thrombophlebitis superficial.
|
|
c Conjunctivitis is a composite term
that includes conjunctivitis, eye irritation, vision blurred, conjunctivitis
bacterial, dry eye, visual acuity reduced, blepharitis, allergic blepharitis,
conjunctiva hemorrhage, eye infection, eye pain, lacrimation increased,
ocular hyperemia, Sjogren's syndrome, visual impairment, and eye pruritus.
|
|
Adverse Reactions (MedDRA)
System Organ Class
|
Portrazza PLUS GEMCITABINE AND CISPLATIN
N=538 (%)
|
GEMCITABINE AND CISPLATIN
N=541 (%)
|
|
All Grades
(Frequency %)
|
Grade 3-4
(Frequency %)
|
All Grades
(Frequency %)
|
Grade 3-4
(Frequency %)
|
|
Skin and Subcutaneous Tissue Disorders
|
|
|
|
|
|
Rash
|
44
|
4
|
6
|
0.2
|
|
Dermatitis
Acneiform
|
15
|
1
|
0.6
|
0
|
|
Acne
|
9
|
0.4
|
0.6
|
0
|
|
Pruritus
|
7
|
0.2
|
0.9
|
0.2
|
|
Dry
Skin
|
7
|
0
|
1
|
0
|
|
Skin
fissures
|
5
|
0.4
|
0
|
0
|
|
Gastrointestinal Disorders
|
|
|
|
|
|
Vomiting
|
29
|
3
|
25
|
0.9
|
|
Diarrhea
|
16
|
2
|
11
|
1
|
|
Stomatitis
|
11
|
1
|
6
|
0.6
|
|
Investigations
|
|
|
|
|
|
Weight
decreased
|
13
|
0.7
|
6
|
0.6
|
|
Respiratory, Thoracic and Mediastinal Disorders
|
|
|
|
|
|
Hemoptysis
|
10
|
1
|
5
|
0.9
|
|
Pulmonary
embolisma
|
5
|
4
|
2
|
2
|
|
Nervous System Disorders
|
|
|
|
|
|
Headache
|
11
|
0
|
6
|
0.4
|
|
Vascular Disorders
|
|
|
|
|
|
Venous
Thromboembolic Events (VTE)b
|
9
|
5
|
5
|
3
|
|
Infections and Infestations
|
|
|
|
|
|
Paronychia
|
7
|
0.4
|
0.2
|
0
|
|
Eye Disorders
|
|
|
|
|
|
Conjunctivitisc
|
7
|
0.4
|
2
|
0
|
Clinically relevant adverse
reactions (all grades) reported in ≥1% and <5% of patients treated with
Portrazza were: dysphagia (3%), oropharyngeal pain (1%), muscle spasms (2%),
phlebitis (2%), and hypersensitivity/IRR (1.5%).
In Study 1, 12% of the patients
on the Portrazza arm discontinued study treatment due to an adverse reaction.
The most common Portrazza related toxicity leading to Portrazza discontinuation
was skin rash (1%).
Table 2 contains selected electrolyte abnormalities observed in
Study 1 according to laboratory assessment at an incidence of >10% in the
Portrazza arm and at >2% higher incidence than the control arm.
The median time to onset of
hypomagnesemia was 6 weeks (25th percentile 4 weeks; 75th percentile 9 weeks).
Hypomagnesemia was reported as resolved in 43% of the patients who received
Portrazza. In Study 1, 32% of the patients in the Portrazza arm and 16% of the
patients who received gemcitabine and cisplatin alone received magnesium
replacement.
Table 2: Electrolyte Abnormalities
according to Laboratory Assessment at Incidence Rate >10% and a >2%
Difference between Arms in Patients Receiving Portrazza in Study 1a
|
|
a Only patients with baseline and at
least one post-baseline result are included.
|
|
LABORATORY PARAMETER
|
Portrazza PLUS GEMCITABINE AND CISPLATIN
N=538
|
GEMCITABINE AND CISPLATIN
N=541
|
|
Na
|
All Grades
(Frequency %)
|
Grade 3 or 4
(Frequency %)
|
Na
|
All Grades
(Frequency %)
|
Grade 3 or 4
(Frequency %)
|
|
Hypomagnesemia
|
461
|
83
|
20
|
457
|
70
|
7
|
|
Hypokalemia
|
505
|
28
|
5
|
505
|
18
|
3
|
|
Hypocalcemia
|
502
|
45
|
6
|
499
|
30
|
2
|
|
Hypocalcemia
(albumin corrected)
|
477
|
36
|
4
|
480
|
23
|
2
|
|
Hypophosphatemia
|
462
|
31
|
8
|
454
|
23
|
6
|
Immunogenicity
As with all therapeutic
proteins, there is the potential for immunogenicity. In clinical trials,
treatment-emergent anti-necitumumab antibodies (ADA) were detected in 4.1%
(33/814) of patients using an enzyme-linked immunosorbent assay (ELISA).
Neutralizing antibodies were detected in 1.4% (11/814) of patients post
exposure to Portrazza. No relationship was found between the presence of ADA
and incidence of infusion-related reactions. The impact of ADA on efficacy
(overall survival) could not be assessed due to the limited number of patients
with treatment-emergent ADA. In Study 1, the exposure to necitumumab was lower
in patients with ADA post-treatment than in patients without detectable
ADA [see Clinical Pharmacology (12.3)].
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 Portrazza with the incidences of antibodies to other products
may be misleading.
USE IN SPECIFIC POPULATIONSPregnancy
Risk Summary
Based on animal data and its
mechanism of action, Portrazza can cause fetal harm when administered to a
pregnant woman [see Clinical Pharmacology (12.1)]. Disruption or depletion
of EGFR in animal models results in impairment of embryo-fetal development
including effects on placental, lung, cardiac, skin, and neural development.
The absence of EGFR signaling has resulted in embryolethality as well as post-natal
death in animals (see Data). No animal
reproduction studies have been conducted with necitumumab. There are no
available data for Portrazza exposure in pregnant women. Advise pregnant women
of the potential risk to a fetus, and the risk to postnatal development.
In the U.S. general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data
Animal Data
No animal studies have been
conducted to evaluate the effect of necitumumab on reproduction and fetal
development; however, based on its mechanism of action, Portrazza can cause
fetal harm or developmental anomalies. In mice, EGFR is critically important in
reproductive and developmental processes including blastocyst implantation,
placental development, and embryo-fetal/postnatal survival and development.
Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent
implantation, can cause embryo-fetal loss during various stages of gestation
(through effects on placental development) and can cause developmental
anomalies and early death in surviving fetuses. Adverse developmental outcomes
were observed in multiple organs in embryos/neonates of mice with disrupted
EGFR signaling. Human IgG1 is known to cross the placenta; therefore,
necitumumab has the potential to be transmitted from the mother to the
developing fetus.
In monkeys, administration of
a chimeric anti-EGFR antibody that binds to an epitope overlapping that of
necitumumab during the period of organogenesis resulted in detectable exposure
of the antibody in the amniotic fluid and in the serum of embryos from treated
dams. While no fetal malformations or other clear teratogenic effects occurred
in offspring, there was an increased incidence of embryolethality and
abortions.
Lactation
Risk Summary
There is no information
regarding the presence of necitumumab in human milk, the effects on the
breastfed infant, or the effects on milk production. Because of the potential
for serious adverse reactions in breastfed infants from Portrazza, advise a
nursing woman not to breastfeed during treatment with Portrazza and for three
months following the final dose.
Females and
Males of Reproductive Potential
Contraception
Females
Based on its mechanism of
action, Portrazza can cause fetal harm when administered to a pregnant
woman [see Use in Specific Populations (8.1)]. Advise females of
reproductive potential to use effective contraception during treatment with
Portrazza and for three months following the final dose.
Pediatric Use
The safety and effectiveness
of Portrazza have not been established in pediatric patients.
Geriatric Use
Of the 545 patients in the
Portrazza plus gemcitabine and cisplatin arm in Study 1, 213 (39%) were 65
years and over, while 108 (20%) were 70 years and over. In an exploratory
subgroup analysis of Study 1, the hazard ratio for overall survival in patients
70 years or older was 1.03 (95% CI: 0.75, 1.42). Of the adverse reactions
listed in Table 1 [see Adverse Reactions (6.1)], there was a higher incidence
(≥3%) of venous thromboembolic events including pulmonary embolism in patients
age 70 and over compared to those who were younger than age 70.
Renal
Impairment
No formal studies have been
conducted to evaluate the effect of renal impairment on the exposure to
necitumumab. Renal function has no influence on the exposure to necitumumab
based on the population pharmacokinetic analysis of data from clinical trials [see Clinical Pharmacology (12.3)].
Hepatic
Impairment
No formal studies have been
conducted to evaluate the effect of hepatic impairment on the exposure to
necitumumab. Mild or moderate hepatic impairment has no influence on the
exposure to necitumumab based on the population pharmacokinetic analysis. No
patients with severe hepatic impairment were enrolled in the clinical trials
with Portrazza [see Clinical Pharmacology (12.3)].
Overdosage
There has been limited
experience with Portrazza overdose in human clinical trials.
The highest dose of Portrazza
studied clinically in a human dose-escalation Phase 1 study was 1000 mg
once a week and once every other week. Two out of 9 patients in the every other
week cohort experienced dose-limiting toxicities (e.g., a combination of Grade
3 headache, vomiting, and nausea). There is no known antidote for Portrazza overdose.
Portrazza Description
Necitumumab is an anti-EGFR
recombinant human monoclonal antibody of the IgG1 kappa isotype that
specifically binds to the ligand binding site of the human EGFR. Necitumumab
has an approximate molecular weight of 144.8 kDa. Necitumumab is produced
in genetically engineered mammalian NS0 cells.
Portrazza is a sterile,
preservative free, clear to slightly opalescent and colorless to slightly
yellow solution. Portrazza is available in single-dose vials for intravenous
infusion following dilution. Each vial contains 800 mg Portrazza in
50 mL (16 mg/mL).
Each mL contains necitumumab
(16 mg), citric acid anhydrous (0.256 mg), glycine (9.984 mg),
mannitol (9.109 mg), polysorbate 80 (0.1 mg), sodium chloride
(2.338 mg), sodium citrate dihydrate (2.55 mg), and water for
injection, pH 6.0.
Portrazza - Clinical PharmacologyMechanism of
Action
Necitumumab is a recombinant
human lgG1 monoclonal antibody that binds to the human epidermal growth factor
receptor (EGFR) and blocks the binding of EGFR to its ligands. Expression and
activation of EGFR has been correlated with malignant progression, induction of
angiogenesis, and inhibition of apoptosis. Binding of necitumumab induces EGFR
internalization and degradation in vitro. In vitro, binding of necitumumab also
led to antibody-dependent cellular cytotoxicity (ADCC) in EGFR-expressing
cells.
In in vivo studies using
xenograft models of human cancer, including non-small cell lung carcinoma,
administration of necitumumab to implanted mice resulted in increased antitumor
activity in combination with gemcitabine and cisplatin as compared to mice
receiving gemcitabine and cisplatin alone.
Pharmacokinetics
Based on population
pharmacokinetic (popPK) analysis of serum concentration data from patients in
clinical studies with Portrazza, necitumumab exhibits dose-dependent kinetics.
Following the administration of Portrazza 800 mg on Days 1 and 8 of each
21 day cycle, the estimated mean total systemic clearance (CLtot) at steady state is
14.1 mL/h (CV=39%), the steady state volume of distribution (Vss) is 7.0 L (CV=31%) and
the elimination half-life is approximately 14 days. The predicted time to reach
steady state is approximately 100 days.
Specific
Populations
Effect of Age, Body Weight, Sex and Race:
Based on the popPK analysis
with data obtained in 807 patients, age (range 19-84 years), sex (75% males),
and race (85% Whites) have no effect on the systemic exposure of necitumumab.
Body weight is identified as a
covariate in the popPK analysis; however, weight-based dosing is not expected
to significantly decrease the variability in exposure. No dose adjustment based
on body weight is necessary.
Renal Impairment
Patients with Renal Impairment
— PopPK analysis did not identify a correlation between necitumumab exposure
and renal function as assessed by estimated creatinine clearance ranging from
11-250 mL/min.
Hepatic Impairment
Patients with Hepatic
Impairment — PopPK analysis did not identify a correlation between the exposure
of necitumumab and hepatic function as assessed by alanine aminotransferase
(ranging from 2-615 U/L), aspartate transaminase (ranging from
1.2-619 U/L) and total bilirubin (ranging from 0.1-106 μmol/L).
Drug
Interactions
Effect of Necitumumab on Gemcitabine and Cisplatin
In 12 patients with advanced
solid tumors who received gemcitabine and cisplatin in combination with
Portrazza, the geometric mean dose-normalized AUC of gemcitabine was increased
by 22% and Cmaxincreased by 63% compared to administration of gemcitabine and
cisplatin alone while exposure to cisplatin was unchanged.
Effect of Gemcitabine and Cisplatin on Necitumumab
Concomitant administration of
gemcitabine and cisplatin had no effect on the exposure of necitumumab.
Immunogenicity
In Study 1, the CLtot of necitumumab was 26%
higher and Css,ave was 34% lower in patients who tested positive for
anti-necitumumab antibodies (ADA) post-treatment than patients who tested
negative for ADA post-treatment.
Nonclinical ToxicologyCarcinogenesis,
Mutagenesis, Impairment of Fertility
No studies have been performed
to assess the potential of necitumumab for carcinogenicity or genotoxicity.
Fertility studies have not
been performed with necitumumab.
Clinical StudiesSquamous
Non-Small Cell Lung Cancer
Study 1 was a randomized,
multi-center open-label, controlled trial conducted in 1093 patients receiving
gemcitabine and cisplatin first-line chemotherapy for metastatic squamous
NSCLC. Patients were randomized (1:1) to receive Portrazza plus gemcitabine and
cisplatin or gemcitabine and cisplatin alone. Stratification factors were ECOG
performance status (0, 1 versus 2) and geographic region (North America,
Europe, and Australia versus South America, South Africa, and India versus
Eastern Asia). Gemcitabine (1250 mg/m2, Days 1 and 8) plus cisplatin
(75 mg/m2, Day 1) were administered every 3 weeks (1 cycle) for a maximum
of 6 cycles in the absence of disease progression or unacceptable toxicity.
Portrazza (800 mg by intravenous infusion on Days 1 and 8 of each 3-week
cycle) was administered prior to gemcitabine and cisplatin. Patients
demonstrating at least stable disease on Portrazza plus gemcitabine and
cisplatin were to continue Portrazza as a single agent in the absence of
disease progression or unacceptable toxicity after completion of 6 planned
courses of chemotherapy or if chemotherapy was discontinued for toxicity.
Of the 1093 randomized
patients, the median age was 62 years (range 32 to 86), 83% were male; 84% were
Caucasian; and 91% were smokers. The majority of the patients (87%) were
enrolled in North America, Europe and Australia, 36 patients (3%) were enrolled
at clinical sites in the U.S., 6% of the patients were enrolled in South
America, South Africa and India and 8% enrolled at clinical sites in Eastern
Asia. Baseline ECOG performance status was 0 or 1 for 91%, and 2 for 9% of
patients; 91% had metastatic disease in 2 or more sites. In the Portrazza plus
gemcitabine and cisplatin arm, 51% of patients continued Portrazza after
completion or discontinuation of chemotherapy. Use of post-study systemic
therapy was 47% in the Portrazza plus gemcitabine and cisplatin arm, and 45% in
the gemcitabine and cisplatin arm.
The main outcome measure was
overall survival (OS). Investigator-assessed progression-free survival (PFS)
and overall response rate (ORR) were also assessed. Overall survival and PFS
were statistically significantly improved in patients randomized to receive
Portrazza plus gemcitabine and cisplatin compared to gemcitabine and cisplatin
alone. There was no difference in ORR between arms, with an ORR of 31% (95% CI
27, 35) for Portrazza plus gemcitabine and cisplatin arm and an ORR of 29% (95%
CI 25, 33) for gemcitabine and cisplatin arm, p-value 0.40.
Efficacy results are shown
in Table 3 and Figure 1.
Table 3: Efficacy Results for Metastatic
Squamous Non-Small Cell Lung Cancer
|
|
a Abbreviations: CI = confidence
interval
|
|
b Investigator assessed
|
|
|
Portrazza PLUS GEMCITABINE AND CISPLATIN
N=545
|
GEMCITABINE AND CISPLATIN
N=548
|
|
Overall Survival
|
|
Number
of deaths (%)
|
418 (77%)
|
442 (81%)
|
|
Median
– months (95% CI)a
|
11.5 (10.4, 12.6)
|
9.9 (8.9, 11.1)
|
|
Stratified
Hazard Ratio (95% CI)
|
0.84 (0.74, 0.96)
|
|
Stratified
Log-rank p-value
|
0.01
|
|
Progression-Free Survivalb
|
|
Number
of events (%)
|
431 (79%)
|
417 (76%)
|
|
Median
– months (95% CI)
|
5.7 (5.6, 6.0)
|
5.5 (4.8, 5.6)
|
|
Stratified
Hazard Ratio (95% CI)
|
0.85 (0.74, 0.98)
|
|
Stratified
Log-rank p-value
|
0.02
|
Figure
1: Kaplan-Meier Curves of Overall Survival in Patients with Metastatic Squamous
Non-Small Cell Lung Cancer
Non-Squamous
NSCLC - Lack of Efficacy
Lack of efficacy of Portrazza
in combination with pemetrexed and cisplatin for the treatment of patients with
metastatic non-squamous non-small cell lung cancer was determined in one
randomized, open-label, multicenter trial (Study 2). The study was closed
prematurely after 633 patients were enrolled due to increased incidence of
death due to any cause and of thromboembolic events in the Portrazza arm.
Patients with no prior chemotherapy for metastatic disease were randomized
(1:1) to receive Portrazza plus pemetrexed and cisplatin or pemetrexed and cisplatin
alone. Stratification factors were smoking status (non-smokers versus light
smokers versus smokers), ECOG performance status (0 - 1 versus 2), histology
(adenocarcinoma/large cell versus others), and geographic region. Portrazza
(800 mg, Days 1 and 8 of each 3-week cycle) was administered prior to
pemetrexed and cisplatin. Patients demonstrating at least stable disease on
Portrazza plus pemetrexed and cisplatin were to continue Portrazza as a single
agent in the absence of disease progression or unacceptable toxicity after
completion of 6 planned courses of chemotherapy.
Of the 633 patients, 315 were
randomized to Portrazza plus pemetrexed and cisplatin arm and 318 in the
pemetrexed and cisplatin arm. The median age was 61 years, 67 % were male, 93%
were Caucasian and 94% had ECOG PS 0 or 1. More than 75% were smokers and 89%
had adenocarcinoma histology.
The main efficacy outcome was
OS. Progression-free survival and ORR were also assessed. Addition of Portrazza
to pemetrexed and cisplatin did not improve OS [HR=1.01; 95%CI (0.84, 1.21);
p-value = 0.96)]; PFS [HR=0.96; 95% CI (0.8, 1.16)] or ORR (31% in the
Portrazza plus pemetrexed and cisplatin arm and 32% in the pemetrexed and
cisplatin alone arm).
How Supplied/Storage and HandlingHow Supplied
Portrazza is supplied in
single-dose vials as a sterile, preservative-free solution:
·
800 mg/50 mL
(16 mg/mL) NDC
0002-7716-01
Storage and
Handling
Store vials in a refrigerator
at 2° to 8°C (36° to 46°F) until time of use. Keep the vial in the outer carton
in order to protect from light. DO NOT FREEZE OR SHAKE the vial.
Patient Counseling Information
Hypomagnesemia
Advise patients of risk of
decreased blood levels of magnesium, potassium and calcium. Take medicines to
replace the electrolytes exactly as advised by the physician. [see Boxed Warning and Warnings and Precautions (5.2)]
Venous
and Arterial Thromboembolic Events
Advise patients of increased
risk of venous and arterial thromboembolic events [see
Warnings and Precautions (5.3)].
Skin
reactions
Advise patients to minimize
sun exposure with protective clothing and use of sunscreen while receiving
Portrazza [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)].
Infusion-Related
Reactions
Advise patients to report
signs and symptoms of infusion reactions such as fever, chills, or breathing
problems [see Warnings and Precautions (5.5)].
Embryo-Fetal
Toxicity
Advise pregnant women of the
potential risk to a fetus [see Use in Specific
Populations (8.1)].
Advise females of reproductive
potential to use effective contraception during treatment with Portrazza and
for three months following final dose [see Use in
Specific Populations (8.3)].
Lactation
Advise women not to breastfeed
during treatment with Portrazza and for three months following the final
dose [see Use in Specific Populations (8.2)].
Literature issued November
2015
Manufactured
by: Eli Lilly and Company, Indianapolis, IN 46285
US License No. 1891
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 2015, Eli Lilly
and Company. All rights reserved.
POR-0001-USPI-20151124
Portrazza 800mg Single Dose Vial
Rx only
NDC 0002-7716-01
Portrazza™
(necitumumab) injection
800 mg/50 mL
(16 mg/mL)
For Intravenous Infusion Only
Must Dilute Prior to Use
Single-Dose Vial
Discard Unused Portion
Keep Refrigerated
Portrazza.com
Lilly
|
Portrazza necitumumab solution
|
|
Product Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0002-7716
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
necitumumab (necitumumab)
|
necitumumab
|
16 mg
in 1 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
Anhydrous Citric Acid
|
0.256 mg
in 1 mL
|
|
Glycine
|
9.984 mg
in 1 mL
|
|
Mannitol
|
9.109 mg
in 1 mL
|
|
Polysorbate 80
|
0.1 mg
in 1 mL
|
|
Sodium Chloride
|
2.338 mg
in 1 mL
|
|
Trisodium Citrate Dihydrate
|
2.55 mg
in 1 mL
|
|
Water
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0002-7716-01
|
1 VIAL,
SINGLE-USE in 1 CARTON
|
|
|
1
|
|
50 mL in 1
VIAL, SINGLE-USE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
BLA
|
BLA125547
|
11/24/2015
|
|
|
|
Labeler - Eli Lilly and Company (006421325)
|
|
Revised:
05/2017
Eli Lilly and Company
vvv
