Imfinzi
Generic
Name: durvalumab
Dosage Form: injection, solution
Indications and Usage for Imfinzi
Imfinzi is indicated for the
treatment of patients with locally advanced or metastatic urothelial carcinoma
who:
•
have disease progression
during or following platinum-containing chemotherapy.
•
have disease progression
within 12 months of neoadjuvant or adjuvant treatment with platinum-containing
chemotherapy.
This
indication is approved under accelerated approval based on tumor response rate
and duration of response. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials [see Clinical
Studies (14.1)].
Imfinzi Dosage and
Administration
Recommended Dosing
The
recommended dose of Imfinzi is 10 mg/kg administered as an intravenous infusion
over 60 minutes every 2 weeks until disease progression or unacceptable
toxicity.
Dose Modifications
No
dose reductions are recommended. Withhold and/or discontinue Imfinzi to manage
adverse reactions as described in Table 1.
Table 1. Recommended Treatment Modifications for Imfinzi
|
|
Adverse Reactions
|
Severitya
|
Imfinzi Treatment Modification
|
Corticosteroid Treatment Unless Otherwise Specified
|
|
Pneumonitis [see Warnings and Precautions (5.1)]
|
Grade 2
|
Withhold doseb
|
Initial dose of 1 mg/kg/day to 2 mg/kg/day
prednisone or equivalent followed by a taper
|
|
Grade 3 or 4
|
Permanently discontinue
|
Initial dose of 1 mg/kg/day to 4 mg/kg/day
prednisone or equivalent followed by a taper
|
|
Hepatitis [see Warnings and Precautions (5.2)]
|
Grade 2 ALT or AST >3‑5xULN or total bilirubin
>1.5-3xULN
|
Withhold doseb
|
Initial dose of 1 mg/kg/day to 2 mg/kg/day
prednisone or equivalent followed by a taper
|
|
Grade 3 ALT or AST ≤8xULN or total bilirubin ≤5xULN
|
|
Grade 3 ALT or AST >8xULN or total bilirubin
>5xULN
|
Permanently discontinue
|
|
Concurrent ALT or AST >3xULN and total bilirubin
>2xULN with no other cause
|
|
Colitis or diarrhea [see Warnings and Precautions (5.3)]
|
Grade 2
|
Withhold doseb
|
Initial dose of 1 mg/kg/day to 2 mg/kg/day
prednisone or equivalent followed by a taper
|
|
Grade 3 or 4
|
Permanently discontinue
|
|
Hypothyroidism [see Warnings and Precautions (5.4)]
|
Grade 2-4
|
|
Initiate thyroid hormone replacement as clinically
indicated
|
|
Hyperthyroidism [see Warnings and Precautions (5.4)]
|
Grade 2-4
|
Withhold dose until clinically stable
|
Symptomatic management
|
|
Adrenal insufficiency, Hypophysitis/Hypopituitarism [see Warnings and Precautions (5.4)]
|
Grade 2-4
|
Withhold dose until clinically stable
|
Initiate 1 to 2 mg/kg/day prednisone or equivalent
followed by a taper and hormone replacement as clinically indicated
|
|
Type 1 Diabetes Mellitus [see Warnings and Precautions (5.4)]
|
Grade 2-4
|
Withhold dose until clinically stable
|
Initiate treatment with insulin as clinically
indicated
|
|
Nephritis [see Warnings and Precautions (5.5)]
|
Grade 2 Creatinine >1.5-3x ULN
|
Withhold doseb
|
Initial dose of 1 mg/kg/day to 2 mg/kg/day
prednisone or equivalent followed by a taper
|
|
Grade 3 Creatinine >3-6x ULN
|
Permanently discontinue
|
|
Grade 4 Creatinine >6x ULN
|
|
Rash or dermatitis [see Warnings and Precautions (5.5)]
|
Grade 2 for >1 week
|
Withhold doseb
|
Consider initial dose of 1 mg/kg/day to 2
mg/kg/day prednisone or equivalent followed by a taper
|
|
Grade 3
|
|
Grade 4
|
Permanently discontinue
|
|
Infection [see Warnings and Precautions (5.6)]
|
Grade 3 or 4
|
Withhold dose
|
Symptomatic management; treat with anti-infectives
for suspected or confirmed infections
|
|
Infusion-related reactions [see Warnings and Precautions (5.7)]
|
Grade 1 or 2
|
Interrupt or slow the rate of infusion
|
Consider pre-medications with subsequent doses
|
|
Grade 3 or 4
|
Permanently discontinue
|
|
|
Other
|
Grade 3
|
Withhold doseb
|
Symptomatic management
|
|
Grade 4
|
Permanently discontinue
|
Consider initial dose of 1 mg/kg/day to 4
mg/kg/day prednisone or equivalent followed by taper
|
|
a Common Terminology Criteria for Adverse
Events, version 4.03. ALT: alanine aminotransferase; AST: aspartate
aminotransferase; ULN: upper limit of normal.
b Based on severity of the adverse
reactions, Imfinzi should be withheld and corticosteroids administered.
Consider increasing dose of corticosteroids and/or other systemic
immunosuppressants if there is worsening or no improvement. Corticosteroid
taper should be initiated when adverse reaction improves to < Grade 1 and
should be continued over at least 1 month. For adverse reactions that do not
result in permanent discontinuation, resume treatment when adverse reaction
returns to ≤ Grade 1 and the corticosteroid dose has been reduced to <10
mg prednisone or equivalent per day.
|
Preparation and Administration
Preparation
•
Visually inspect drug product for
particulate matter and discoloration. Imfinzi is clear to opalescent, colorless
to slightly yellow solution, free from visible particles. Discard the vial if
the solution is cloudy, discolored, or visible particles are observed.
•
Do not shake the vial.
•
Withdraw the required volume from the
vial(s) of Imfinzi and transfer into an intravenous bag containing 0.9% Sodium
Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by
gentle inversion. Do not shake the solution. The final concentration of the
diluted solution should be between 1 mg/mL and 15 mg/mL.
•
Discard partially used or empty vials of
Imfinzi.
Storage of Infusion Solution
Imfinzi does not contain a preservative.
Administer infusion solution immediately
once prepared. If infusion solution is not administered immediately and needs
to be stored, the total time from vial puncture to the start of the
administration should not exceed:
•
24 hours in a refrigerator at 2°C to 8°C
(36°F to 46°F)
•
4 hours at room temperature up to 25°C
(77°F)
Do not freeze.
Do not shake.
Administration
•
Administer infusion solution intravenously
over 60 minutes through an intravenous line containing a sterile, low-protein
binding 0.2 or 0.22 micron in-line filter.
•
Do not co-administer other drugs through
the same infusion line.
Dosage Forms and Strengths
Injection: 120 mg/2.4mL (50 mg/mL) and 500
mg/10mL (50 mg/mL) clear to opalescent, colorless to slightly yellow solution
in a single-dose vial.
Contraindications
None.
Warnings and Precautions
Immune-Mediated Pneumonitis
Immune-mediated pneumonitis or interstitial
lung disease occurred in patients receiving Imfinzi. Monitor patients for signs
and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with
radiographic imaging and manage with treatment modifications and
corticosteroids [see Dosage and
Administration (2.2)].
In Study 1 (n=182), one patient (0.5%) died
from immune-mediated pneumonitis. In the combined safety database (n=1414), of
patients treated with Imfinzi 10 mg/kg every 2 weeks, immune-mediated
pneumonitis occurred in 32 (2.3%) patients including fatal pneumonitis in one
(0.1%) patient and Grade 3-4 in six (0.4%) patients. The median time to onset
was 55.5 days (range: 24-423 days). Seventeen (1.2%) patients received
high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per
day). Imfinzi was interrupted in 12 patients and discontinued in five (0.4%)
patients. Resolution occurred in 18 (1.3%) patients.
Immune-Mediated Hepatitis
Immune-mediated hepatitis occurred in
patients receiving Imfinzi. Monitor patients for abnormal liver tests each
cycle during treatment with Imfinzi. Manage immune-mediated hepatitis with
treatment modifications and corticosteroids [see Dosage and
Administration (2.2)].
In Study 1, one (0.5%) patient died from
immune-mediated hepatitis. An additional two (1.1%) patients experienced
immune-mediated hepatitis, including Grade 3 in one (0.5%) patient. In the
combined safety database, immune-mediated hepatitis occurred in 16 (1.1%)
patients including fatal hepatitis in one (<0.1%) patient and Grade 3 in
nine (0.6%) patients. The median time to onset was 51.5 days (range: 15-312
days). Twelve (0.8%) of the 16 patients received high-dose corticosteroid
treatment. One patient also received mycophenolate treatment. Imfinzi was
interrupted in five (0.3%) patients and discontinued in three (0.2%) patients.
Resolution occurred in nine (0.6%) patients. In the combined safety database,
Grade 3 or 4 elevations in ALT occurred in 40/1342 (3.0%) of patients, AST in
58/1336 (4.3%), and total bilirubin in 37/1341 (2.8%) of patients.
5.3 Immune-Mediated Colitis
Immune-mediated colitis or
diarrhea occurred in patients receiving Imfinzi. Monitor patients for signs and
symptoms of colitis or diarrhea and manage with treatment modifications,
anti-diarrheal agents, and corticosteroids [see Dosage
and Administration (2.2)].
In Study 1, colitis or
diarrhea occurred in 23 (12.6%) patients including Grade 3 or 4 diarrhea in two
(1.1%) patients. No patients in Study 1 received systemic corticosteroids or
immunosuppressants for diarrhea or colitis. In the combined safety database,
immune-mediated colitis or diarrhea occurred in 18 (1.3%) patients including
Grade 4 in one (<0.1%) and Grade 3 in four (0.3%) patients. The median time
to onset was 73 days (range: 13-345 days). Of these patients, one (<0.1%)
had Grade 4 and four (0.3%) had Grade 3 immune-mediated colitis or diarrhea.
Ten (0.7%) of the 18 patients received high-dose corticosteroid treatment. Two
(0.1%) patients received non-steroidal immunosuppressants. Imfinzi was
interrupted in five (0.4%) patients and discontinued in six (0.4%) patients.
Resolution occurred in 11 (0.8%) patients.
Immune-Mediated
Endocrinopathies
Immune-related thyroid
disorders, adrenal insufficiency, type 1 diabetes mellitus and
hypophysitis/hypopituitarism have occurred in patients receiving Imfinzi. Monitor
patients for clinical signs and symptoms of endocrinopathies.
Thyroid
Disorders
Monitor thyroid function prior
to and periodically during treatment with Imfinzi. Asymptomatic patients with
abnormal thyroid function tests can receive Imfinzi. Manage patients with
abnormal thyroid function tests with hormone replacement (if indicated) and
treatment modifications [see Dosage
and Administration (2.2)].
In the Study 1, hypothyroidism
or thyroiditis leading to hypothyroidism occurred in ten (5.5%) patients. All
patients had Grade 1-2 hypothyroidism. The median time to first onset was 42
days (range: 15-239). Thyroid stimulating hormone (TSH) was elevated and above
the patient’s baseline in 25 (15.3%) of 163 patients with a follow-up
measurement.
In Study 1, hyperthyroidism or
thyroiditis leading to hyperthyroidism occurred in nine (4.9%) patients. All
patients had Grade 1-2 hyperthyroidism. The median time to first onset was 43
days (range: 14-71). Thyroid stimulating hormone (TSH) was decreased and below
the patient’s baseline in 26 (16%) of 163 patients with a follow-up
measurement.
In the combined safety
database, hypothyroidism occurred in 136 (9.6%) patients, while hyperthyroidism
occurred in 81 (5.7%) patients. Thyroiditis occurred in ten patients, including
Grade 3 in one patient who had a myocardial infarction. In nine patients with
thyroiditis, transient hyperthyroidism preceded hypothyroidism. Treatment with
a beta-blocker and/or thioamide was administered for hyperthyroidism in five of
these patients.
Adrenal
Insufficiency
Monitor patients for clinical
signs and symptoms of adrenal insufficiency. Administer corticosteroids and
hormone replacement as clinically indicated [see Dosage
and Administration (2.2)].
In Study 1, adrenal
insufficiency occurred in one (0.5%) patient (Grade 1). In the combined safety
database, adrenal insufficiency occurred in 13 (0.9%) patients, including Grade
3 in two (0.1%) patients. Seven (0.5%) of these patients were treated with
systemic corticosteroids.
Type 1
Diabetes Mellitus
Monitor patients for
hyperglycemia or other signs and symptoms of diabetes. Initiate insulin for
type 1 diabetes mellitus and manage patients with treatment modifications [see Dosage
and Administration (2.2)]. New onset type 1 diabetes
mellitus without an alternative etiology occurred in one patient (<0.1%) in
the combined safety database.
Hypophysitis
Monitor for signs and symptoms
of hypophysitis or hypopituitarism. Administer corticosteroids and hormone
replacement as clinically indicated [see Dosage
and Administration (2.2)]. Hypopituitarism leading to
adrenal insufficiency and diabetes insipidus occurred in one patient (<0.1%)
in the combined safety database.
Other
Immune-Mediated Adverse Reactions
Imfinzi has caused
immune-mediated rash. Other immune-related adverse reactions, including aseptic
meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis,
myositis, nephritis, and ocular inflammatory toxicity including uveitis and
keratitis, have occurred in ≤1.0% of patients treated with Imfinzi.
Monitor for signs and symptoms
of rash [see Dosage
and Administration (2.2)]. In Study 1, 20 (11.0%) of
patients developed rash including Grade 3 rash in one (0.5%) patient. In the
combined safety database, 220 (15.6%) patients developed rash and four (0.3%)
patients developed vitiligo. Systemic corticosteroids were administered in 17
(1.2%) patients. The rash resolved in 133 (9.4%) patients.
Immune
Thrombocytopenic Purpura
Monitor patients for signs and
symptoms of immune thrombocytopenic purpura [see Dosage
and Administration (2.2)]. In the combined safety
database, immune thrombocytopenic purpura led to death in one (<0.1%)
patient. The patient received high-dose corticosteroids, human immunoglobulin,
and rituximab.
Nephritis
Monitor patients for abnormal
renal function tests prior to and each cycle during treatment with Imfinzi and
manage with treatment modifications and corticosteroids [see Dosage
and Administration (2.2)]. In Study 1, one patient
received systemic corticosteroids for immune-mediated nephritis. In the
combined safety database, immune-mediated nephritis occurred in three (0.2%)
patients including Grade 3 in two (0.1%) patients. All three patients received
high-dose corticosteroids treatment. Imfinzi was discontinued in all three
patients. Resolution occurred in all three patients.
Infection
Severe infections, including
sepsis, necrotizing fasciitis, and osteomyelitis, occurred in patients
receiving Imfinzi. Monitor patients for signs and symptoms of infection and treat
with anti-infectives for suspected or confirmed infections. Withhold Imfinzi
for ≥Grade 3 infection [see Dosage
and Administration (2.2) and Adverse
Reactions (6.1)].
In Study 1, infections
occurred in 54 (29.7%) patients. Grade 3 or 4 infection occurred in eleven
(6.0%) patients, while five (2.7%) patients were experiencing infection at the
time of death. Urinary tract infections were the most common cause of Grade 3
or higher infection, occurring in eight (4.4%) patients. In the combined safety
database, infections occurred in 531 (37.6%) patients.
Infusion-Related
Reactions
Severe infusion-related
reactions have been reported in patients receiving Imfinzi. Monitor for signs
and symptoms of an infusion-related reaction. Interrupt or slow the rate of
infusion in patients with mild or moderate infusion reactions. Permanently
discontinue Imfinzi in patients with Grade 3 or 4 infusion reactions [see Dosage
and Administration (2.2)].
Infusion related reactions occurred
in three (1.6%) patients in Study 1 and 26 (1.8%) patients in the combined
safety database. There were five (0.4%) Grade 3 and no Grade 4 or 5 reactions.
Four (0.3%) patients developed urticaria within 48 hours of dosing.
Embryo-Fetal
Toxicity
Based on its mechanism of
action and data from animal studies, Imfinzi can cause fetal harm when
administered to a pregnant woman. In animal reproduction studies,
administration of durvalumab to cynomolgus monkeys from the onset of
organogenesis through delivery resulted in increased premature delivery, fetal
loss and premature neonatal death. Advise pregnant women of the potential risk
to a fetus. Advise females of reproductive potential to use effective
contraception during treatment with Imfinzi and for at least 3 months after the
last dose of Imfinzi [see Use in
Specific Populations (8.1, 8.3)].
Adverse Reactions
The following adverse reactions are
discussed in greater detail in other sections of the labeling.
•
Immune-Mediated Pneumonitis [see Warnings and
Precautions (5.1)].
•
Immune-Mediated Hepatitis [see Warnings and
Precautions (5.2)].
•
Immune-Mediated Colitis [see Warnings and
Precautions (5.3)].
•
Immune-Mediated
Endocrinopathies [see Warnings and
Precautions (5.4)].
•
Other Immune-Mediated Adverse
Reactions [see Warnings and
Precautions (5.5)].
•
Infection [see Warnings and
Precautions (5.6)].
•
Infusion-Related Reactions [see Warnings and
Precautions (5.7)].
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 data described in
Table 2 reflect exposure to Imfinzi in 182 patients with locally advanced or
metastatic urothelial carcinoma in Study 1 whose disease has progressed during
or after one standard platinum-based regimen. Patients received 10 mg/kg
Imfinzi via intravenous infusion every 2 weeks [see Clinical
Studies (14.1)]. The median duration of exposure was 10.2 weeks (range: 0.14,
52.4).
Thirty-one percent (31%) of
patients had a drug delay or interruption for an adverse reaction. The most
common (>2%) were liver injury (4.9%), urinary tract infection (3.3%), acute
kidney injury (3.3%), and musculoskeletal pain (2.7%).
The most common adverse
reactions (≥15%) were fatigue (39%), musculoskeletal pain (24%), constipation
(21%), decreased appetite (19%), nausea (16%), peripheral edema (15%) and
urinary tract infection (15%). The most common Grade 3 or 4 adverse reactions
(≥3%) were fatigue, urinary tract infection, musculoskeletal pain, abdominal
pain, dehydration, and general physical health deterioration.
Eight patients (4.4%) who were
treated with Imfinzi experienced Grade 5 adverse events of cardiorespiratory
arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or
immune-mediated hepatitis. Three additional patients were experiencing infection
and disease progression at the time of death. Imfinzi was discontinued for
adverse reactions in 3.3% of patients. Serious adverse reactions occurred in
46% of patients. The most frequent serious adverse reactions (>2%) were
acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal
pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%),
sepsis, abdominal pain, pyrexia/tumor associated fever (2.7% each).
Immune-mediated adverse
reactions requiring systemic corticosteroids or hormone replacement therapy
occurred in 8.2% (15/182) patients, including 5.5% (10/182) patients who
required systemic corticosteroid therapy and 2.7% (5/182) patients who required
only hormone replacement therapy. Seven patients (3.8%) received an oral
prednisone dose equivalent to >40 mg daily for an immune-mediated adverse
reaction [see Warnings
and Precautions (5)].
Table 2 summarizes the adverse
reactions that occurred in ≥10% of patients, while Table 3 summarizes the Grade
3 − 4 selected laboratory abnormalities that occurred in ≥1% of patients
treated with Imfinzi in Study 1.
Table 2. Adverse Reactions in ≥10% of Patients in UC Cohort Study 1
|
|
|
Imfinzi
N=182
|
|
Adverse Reaction
|
All Grades
(%)
|
Grades 3 – 4
(%)
|
|
All Adverse Reactions
|
96
|
43
|
|
Gastrointestinal Disorders
|
|
Constipation
|
21
|
1
|
|
Nausea
|
16
|
2
|
|
Abdominal pain1
|
14
|
3
|
|
Diarrhea/Colitis
|
13
|
1
|
|
General Disorders and Administration
|
|
Fatigue2
|
39
|
6
|
|
Peripheral edema3
|
15
|
2
|
|
Pyrexia/Tumor associated fever
|
14
|
1
|
|
Infections
|
|
Urinary tract infection4
|
15
|
4
|
|
Metabolism and Nutrition Disorders
|
|
Decreased appetite/Hypophagia
|
19
|
1
|
|
Musculoskeletal and Connective Tissue
Disorders
|
|
Musculoskeletal pain5
|
24
|
4
|
|
Respiratory, Thoracic, and Mediastinal
Disorders
|
|
Dyspnea/Exertional Dyspnea
|
13
|
2
|
|
Cough/Productive Cough
|
10
|
0
|
|
Skin and Subcutaneous Tissue Disorders
|
|
Rash6
|
11
|
1
|
|
1 Includes abdominal pain upper, abdominal pain
lower and flank pain
2 Includes asthenia, lethargy, and
malaise
3 Includes edema, localized edema,
edema peripheral, lymphedema, peripheral swelling, scrotal edema, and scrotal
swelling
4 Includes cystitis, candiduria and
urosepsis
5 Includes back pain, musculoskeletal
chest pain, musculoskeletal pain and discomfort, myalgia, and neck pain
6 Includes dermatitis, dermatitis
acneiform, dermatitis psoriasiform, psoriasis, rash maculo-papular, rash
pruritic, rash papular, rash pustular, skin toxicity, eczema, erythema,
erythema multiforme, rash erythematous, acne, and lichen planus
|
Table 3. Grade 3-4 Laboratory
Abnormalities Worsened from Baseline Occurring in ≥1% Patients in UC Cohort
Study 1
|
|
Laboratory Test
|
Grade 3 - 4
%
|
|
Hyponatremia
|
12
|
|
Lymphopenia
|
11
|
|
Anemia
|
8
|
|
Increased alkaline phosphatase
|
4
|
|
Hypermagnesemia
|
4
|
|
Hypercalcemia
|
3
|
|
Hyperglycemia
|
3
|
|
Increased AST
|
2
|
|
Increased ALT
|
1
|
|
Hyperbilirubinemia
|
1
|
|
Increased creatinine
|
1
|
|
Neutropenia
|
1
|
|
Hyperkalemia
|
1
|
|
Hypokalemia
|
1
|
|
Hypoalbuminemia
|
1
|
Immunogenicity
As with all therapeutic
proteins, there is a potential for immunogenicity. 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 the
incidence of antibodies to Imfinzi to the incidence of antibodies to other
products may be misleading.
Due to the limitations in
assay performance, the incidence of antibody development in patients receiving
Imfinzi has not been adequately determined. Of 1124 patients who were treated
with Imfinzi 10 mg/kg every 2 weeks and evaluable for the presence of anti-drug
antibodies (ADAs), 3.3% patients tested positive for treatment-emergent ADAs.
The clinical significance of anti-durvalumab antibodies is unknown.
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk summary
Based on its mechanism of
action and data from animal studies, Imfinzi can cause fetal harm when
administered to a pregnant woman [see Clinical
Pharmacology (12.1)]. There are no data on the use
of Imfinzi in pregnant women.
In animal reproduction
studies, administration of durvalumab to pregnant cynomolgus monkeys from the
confirmation of pregnancy through delivery resulted in increased in premature
delivery, fetal loss and premature neonatal death (see
Data). Human immunoglobulin G1 (IgG1) is known to cross the
placental barrier; therefore, durvalumab has the potential to be transmitted
from the mother to the developing fetus. Apprise pregnant women of the
potential risk to a fetus.
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
As reported in the literature,
the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by
maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy
models, disruption of PD-L1 signaling was shown to result in an increase in
fetal loss. The effects of durvalumab on prenatal and postnatal development
were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was
administered from the confirmation of pregnancy through delivery at exposure
levels approximately 6 to 20 times higher than those observed at the clinical
dose of 10 mg/kg of durvalumab (based on AUC). Administration of durvalumab
resulted in premature delivery, fetal loss (abortion and stillbirth) and
increase in neonatal deaths. Durvalumab was detected in infant serum on
postpartum Day 1, indicating the presence of placental transfer of durvalumab.
Based on its mechanism of action, fetal exposure to durvalumab may increase the
risk of developing immune-mediated disorders or altering the normal immune
response and immune-mediated disorders have been reported in PD-1 knockout
mice.
Lactation
Risk Summary
There is no information
regarding the presence of durvalumab in human milk, the effects on the
breastfed infant, or the effects on milk production. Human IgG1 is excreted in
human milk. Durvalumab was present in the milk of lactating cynomolgus monkeys
and was associated with premature neonatal death (see
Data).
Because of the potential for
adverse reactions in breastfed infants from durvalumab, advise a lactating
woman not to breastfeed during treatment with Imfinzi and for at least 3 months
after the last dose.
Data
In lactating cynomolgus
monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum
concentrations after administration of durvalumab from the confirmation of
pregnancy through delivery at exposure levels approximately 6 to 20 times
higher than those observed at the clinical dose of 10 mg/kg of durvalumab
(based on AUC). Administration of durvalumab resulted in premature neonatal
death.
Females and
Males of Reproductive Potential
Contraception
Females
Based on its mechanism of
action, Imfinzi 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
Imfinzi, and for at least 3 months following the last dose of Imfinzi.
Pediatric Use
The safety and effectiveness
of Imfinzi have not been established in pediatric patients.
Geriatric Use
Of the 182 patients treated
with Imfinzi, 112 patients were 65 years or older and 34 patients were 75 years
or older. The overall response rate in patients 65 years or older was 15.2%
(17/112) and was 11.8% (4/34) in patients 75 years or older. Grade 3 or 4
adverse reactions occurred in 38% (42/112) of patients 65 years or older and
35% (12/34) of patients 75 years or older. Study results in patients > 65
years of age and particularly in those > 75 years of age should be viewed
with caution given the small number of patients.
Overdosage
There is no information on
overdose with Imfinzi.
Imfinzi Description
Durvalumab is a human
immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction
of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1)
molecules. Durvalumab is produced by recombinant DNA technology in Chinese
Hamster Ovary (CHO) cell suspension culture.
Imfinzi (durvalumab) Injection
for intravenous use is a sterile, preservative-free, clear to opalescent,
colorless to slightly yellow solution, free from visible particles.
Each 500 mg vial of Imfinzi
contains 500 mg of durvalumab in 10 mL solution. Each mL contains durvalumab,
50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg),
α,α-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for
Injection, USP.
Each 120 mg vial of Imfinzi
contains 120 mg of durvalumab in 2.4 mL solution. Each mL contains durvalumab,
50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg),
α,α-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for
Injection, USP.
Imfinzi - Clinical Pharmacology
Mechanism of
Action
Expression of programmed cell
death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma)
and can be expressed on both tumor cells and tumor-associated immune cells in
the tumor microenvironment. PD-L1 blocks T-cell function and activation through
interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1
reduces cytotoxic T-cell activity, proliferation, and cytokine production.
Durvalumab is a human
immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction
of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80
interactions releases the inhibition of immune responses, without inducing
antibody dependent cell-mediated cytotoxicity (ADCC).
PD-L1 blockade with durvalumab
led to increased T-cell activation in vitro and decreased tumor size in
co-engrafted human tumor and immune cell xenograft mouse models.
Pharmacodynamics
The exposure-response
relationships for efficacy and safety are unknown.
Cardiac
Electrophysiology
Durvalumab is unlikely to
prolong the QT/QTc interval.
Pharmacokinetics
The pharmacokinetics of
durvalumab was studied in 1324 patients with doses ranging from 0.1 mg/kg (0.01
times the approved recommended dosage) to 20 mg/kg (2 times the approved
recommended dosage) administered once every two, three or four weeks.
PK exposure increased more
than dose-proportionally at doses less than 3 mg/kg (0.3 times the approved
recommended dosage) and dose proportionally at doses greater than or equal to 3
mg/kg. Steady state was achieved at approximately 16 weeks.
Distribution
The geometric mean (%
coefficient of variation [CV%]) steady state volume of distribution was 5.6
(17%) L.
Elimination
Durvalumab clearance decreases
over time, with a mean maximal reduction (CV%) from baseline values of
approximately 22.9% (46.3%) resulting in a geometric mean (CV%) steady state
clearance (CLss) of 8.24 mL/h (37.3%); the decrease in CLss is not considered
clinically relevant. The geometric mean (CV%) terminal half-life was
approximately 17 (23.2%) days.
Specific
Populations
Age (19–96 years), body weight
(34-149 kg), sex, albumin levels, lactate dehydrogenase (LDH) levels,
creatinine levels, soluble PD-L1, tumor type, race, mild renal impairment
(creatinine clearance (CLcr) 60 to 89 mL/min), moderate renal impairment (CLcr
30 to 59 mL/min), mild hepatic impairment (bilirubin less than or equal to ULN
and AST greater than ULN or bilirubin greater than 1.0 to 1.5 times ULN and any
AST), or ECOG performance status had no clinically significant effect on the
pharmacokinetics of durvalumab.
The effect of severe renal
impairment (CLcr 15 to 29 mL/min) or moderate hepatic impairment (bilirubin
greater than 1.5 to 3.0 times ULN and any AST) or severe hepatic impairment
(bilirubin greater than 3.0 times ULN and any AST) on the pharmacokinetics of
durvalumab is unknown.
Nonclinical Toxicology
Carcinogenesis,
Mutagenesis, Impairment of Fertility
The carcinogenic and genotoxic
potential of durvalumab have not been evaluated.
Animal fertility studies have
not been conducted with durvalumab. In repeat-dose toxicology studies with
durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration,
there were no notable effects on the male and female reproductive organs.
Animal
Toxicology and/or Pharmacology
In animal models, inhibition
of PD-L1/PD-1 signaling increased the severity of some infections and enhanced
inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit
markedly decreased survival compared with wild-type controls, which correlated
with increased bacterial proliferation and inflammatory responses in these
animals. PD-L1 and PD-1 knockout mice have also shown decreased survival
following infection with lymphocytic choriomeningitis virus.
Clinical StudiesUrothelial
Carcinoma
The efficacy of Imfinzi was
evaluated in Study 1, the urothelial cancer cohort of a multicenter,
multi-cohort, open-label clinical trial. In Study 1, 182 patients with locally
advanced or metastatic urothelial carcinoma were enrolled. Patients had
progressed while on or after a platinum-based therapy, including those who
progressed within 12 months of receiving therapy in a neo-adjuvant or adjuvant
setting. These patients had initiated durvalumab therapy at least 13 weeks
prior to the data cut-off date. The trial excluded patients with a history of
immunodeficiency; medical conditions that required systemic immunosuppression
(not to exceed 10 mg/day of prednisone or equivalent); history of severe
autoimmune disease; untreated CNS metastases; HIV; active tuberculosis, or
hepatitis B or C infection. All patients received Imfinzi 10 mg/kg via
intravenous infusion every 2 weeks for up to 12 months or until unacceptable
toxicity or disease progression. Tumor assessments were performed at Weeks 6,
12 and 16, then every 8 weeks for the first year and every 12 weeks thereafter.
The major efficacy outcome measures were confirmed Objective Response Rate
(ORR) according to RECIST v1.1 as assessed by Blinded Independent Central
Review (BICR), and duration of response (DoR).
In Study 1, the median age was
67 years (range: 34 to 88), 72% were male, 64% were Caucasian. Sixty-six
percent (66%) of patients had visceral metastasis (bone, liver, or lung),
including 34% with liver metastasis. Lymph node only metastasis were present in
13% of patients. Sixty-six percent (66%) of patients had ECOG score of 1 and
41% of patients had a baseline creatinine clearance of <60 mL/min. The
Bellmunt risk score (which includes ECOG score, baseline hemoglobin, and liver
metastases) was 0 in 23%, 1 in 38%, 2 in 29%, and 3 in 9% of patients. Twenty
percent (20%) of patients had disease progression following platinum-containing
neo-adjuvant or adjuvant chemotherapy as their only prior line of therapy.
Seventy percent (70%) of patients received prior cisplatin, 30% prior
carboplatin and 35% received ≥2 prior lines of systemic therapy.
Tumor specimens were evaluated
prospectively for PD-L1 expression on tumor cells (TC) and immune cells (IC) at
a central laboratory using the VENTANA PD-L1 (SP263) Assay. Of the 182
patients, 95 were classified as PD-L1 high (if ICs involve >1% of the tumor
area, TC ≥25% or IC ≥25%; if ICs involve ≤1% of the tumor area, TC ≥25% or IC=100%),
73 as PD-L1 low/negative (did not meet criterion for PD-L1 high), and samples
for 14 patients were not evaluable.
Table 4 summarizes the results
in Study 1. The median follow-up time was 5.6 months. In 37 patients who had
received only neoadjuvant or adjuvant therapy prior to study entry, nine
patients (24%) responded.
Among the total 31 responding
patients, 14 patients (45%) had ongoing responses of 6 months or longer and
five patients (16%) had ongoing responses of 12 months or longer.
Table 4. Efficacy Results for Study 1
|
|
|
All Patients
N = 182
|
PD-L1 High
N = 95
|
PD-L1 Low/Negative
N = 73
|
PD-L1 NE
N = 14
|
|
Objective Response Rate by BICR n (%)
(95% CI)
|
31 (17.0%)
(11.9, 23.3)
|
25 (26.3%)
(17.8, 36.4)
|
3 (4.1%)
(0.9, 11.5)
|
3 (21.4%)
(4.7, 50.8)
|
|
Complete Response
|
5
|
3
|
1
|
1
|
|
Partial Response
|
26
|
22
|
2
|
2
|
|
Median Duration of Response months
(range)
|
NR
(0.9+, 19.9+)
|
NR
(0.9+, 19.9+)
|
12.3
(1.9+, 12.3)
|
NR
(2.3+, 2.6+)
|
|
BICR = Blinded Independent Central Review; NE = Not
Evaluable; NR = Not Reached, + denotes a censored value
|
How Supplied/Storage and Handling
Imfinzi (durvalumab) Injection
is a clear to opalescent, colorless to slightly yellow solution supplied in a
carton containing one single-dose vial either as:
•
500 mg/10 mL (NDC
0310-4611-50)
•
120 mg/2.4 mL (NDC
0310-4500-12)
Store
in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect
from light.
Do not
freeze. Do not shake.
Patient Counseling
Information
Advise
the patient to read the FDA-approved patient labeling (Medication Guide).
Inform
patients of the risk of immune-mediated adverse reactions that may require
corticosteroid treatment and interruption or discontinuation of Imfinzi,
including:
•
Pneumonitis: Advise patients
to contact their healthcare provider immediately for any new or worsening
cough, chest pain, or shortness of breath [see Warnings
and Precautions (5.1)].
•
Hepatitis: Advise patients to
contact their healthcare provider immediately for jaundice, severe nausea or
vomiting, pain on the right side of abdomen, lethargy, or easy bruising or
bleeding [see Warnings
and Precautions (5.2)].
•
Colitis: Advise patients to
contact their healthcare provider immediately for diarrhea, blood or mucus in
stools, or severe abdominal pain [see Warnings
and Precautions (5.3)].
•
Endocrinopathies: Advise
patients to contact their healthcare provider immediately for signs or symptoms
of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis or type
1 diabetes mellitus [see Warnings
and Precautions (5.4)].
•
Other Immune-Mediated Adverse
Reactions: Advise patients to contact their healthcare provider immediately for
signs or symptoms of rash, nephritis, aseptic meningitis, thrombocytopenic
purpura, myocarditis, hemolytic anemia, myositis, uveitis and keratitis [see Warnings
and Precautions (5.5)].
•
Infection: Advise patients to
contact their healthcare provider immediately for infection [see Warnings
and Precautions (5.6)].
•
Infusion-Related Reactions:
Advise patients to contact their healthcare provider immediately for signs or
symptoms of infusion-related reactions [see Warnings
and Precautions (5.7)].
•
Embryo-Fetal Toxicity: Advise
females of reproductive potential that Imfinzi can cause harm to a fetus and to
inform their healthcare provider of a known or suspected pregnancy [see Warnings
and Precautions (5.8) and Use in
Specific Populations (8.1, 8.3)].
Advise females of reproductive potential to use effective contraception during
treatment and for at least 3 months after the last dose of Imfinzi [see Use in
Specific Populations (8.3)].
•
Lactation: Advise female
patients not to breastfeed while taking Imfinzi and for at least 3 months after
the last dose [see Warnings
and Precautions (5.8) and Use in
Specific Populations (8.2)].
Manufactured
for:
AstraZeneca
Pharmaceuticals LP
Wilmington, DE 19850
|
MEDICATION GUIDE
Imfinzi™
(durvalumab)
Injection
|
|
What is the most important information I
should know about Imfinzi?
Imfinzi is a medicine that may treat a
type of cancer in the bladder and urinary tract by working with your immune
system.
In some patients Imfinzi can cause the
immune system to attack normal organs and tissues and can affect the way they
work. These problems can sometimes become serious or life-threatening and can
lead to death.
Call or see your healthcare provider
right away if you develop any symptoms of the following problems or these
symptoms get worse:
Lung problems (pneumonitis). Signs
and symptoms of pneumonitis may include:
•
new or worsening cough
•
shortness of breath
•
chest pain
Liver problems (hepatitis). Signs
and symptoms of hepatitis may include:
•
yellowing of your skin or the whites of
your eyes
•
severe nausea or vomiting
•
pain on the right side of your stomach
area (abdomen)
•
drowsiness
•
dark urine (tea colored)
•
bleeding or bruising more easily than
normal
•
feeling less hungry than usual
Intestinal problems (colitis). Signs
and symptoms of colitis may include:
•
diarrhea or more bowel movements than
usual
•
stools that are black, tarry, sticky, or
have blood or mucus
•
severe stomach area (abdomen) pain or
tenderness
Hormone gland problems (especially the
thyroid, adrenals, pituitary and pancreas). Signs and symptoms that your
hormone glands are not working properly may include:
•
headaches that will not go away or
unusual headaches
•
extreme tiredness
•
weight gain or weight loss
•
dizziness or fainting
•
feeling more hungry or thirsty than usual
•
hair loss
•
feeling cold
•
constipation
•
your voice gets deeper
•
urinating more often than usual
•
nausea or vomiting
•
stomach area (abdomen) pain
•
changes in mood or behavior, such as
decreased sex drive, irritability, or forgetfulness
Kidney problems, including nephritis and
kidney failure. Signs of kidney problems may include:
•
decrease in the amount of urine
•
blood in your urine
•
swelling in your ankles
•
loss of appetite
Skin problems. Signs of these
problems may include:
•
rash
•
itching
•
skin blistering
Problems in other organs. Signs and
symptoms may include:
•
neck stiffness
•
headache
•
confusion
•
fever
•
changes in mood or behavior
•
blurry vision, double vision, or other
vision problems
•
eye pain or redness
Severe Infections. Signs and
symptoms may include:
•
fever
•
cough
•
frequent urination
•
pain when urinating
•
flu-like symptoms
Severe infusion reactions. Signs and
symptoms of severe infusion reactions may include:
•
chills or shaking
•
itching or rash
•
flushing
•
shortness of breath or wheezing
•
dizziness
•
fever
•
feel like passing out
•
back or neck pain
•
facial swelling
Getting medical treatment right away may
help keep these problems from becoming more serious.
Your healthcare provider will check you
for these problems during your treatment with Imfinzi. Your healthcare
provider may treat you with corticosteroid or hormone replacement medicines.
Your healthcare provider may delay or completely stop treatment with Imfinzi,
if you have severe side effects.
|
|
What is Imfinzi?
Imfinzi is a prescription medicine
used to treat a type of cancer in the bladder and urinary tract called
urothelial carcinoma.
Imfinzi may be used when your urothelial
carcinoma:
•
has spread or cannot be removed by
surgery and,
•
you have tried chemotherapy that contains
platinum, and it did not work or is no longer working.
It is not known if Imfinzi is safe and
effective in children.
|
|
Before you receive Imfinzi, tell your
healthcare provider about all of your medical conditions, including if you:
•
have immune system problems such as
Crohn’s disease, ulcerative colitis, or lupus
•
have had an organ transplant
•
have lung or breathing problems
•
have liver problems
•
are being treated for an infection
•
are pregnant or plan to become pregnant.
Imfinzi can harm your unborn baby. If you are able to become pregnant, you
should use an effective method of birth control during your treatment and for
at least 3 months after the last dose of Imfinzi. Talk to your healthcare
provider about birth control methods that you can use during this time. Tell
your healthcare provider right away if you become pregnant during treatment
with Imfinzi.
•
are breastfeeding or plan to breastfeed.
It is not known if Imfinzi passes into your breast milk. Do not breastfeed
during treatment and for at least 3 months after the last dose of Imfinzi.
Tell your healthcare provider about all
the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
|
|
How will I receive Imfinzi?
•
Your healthcare provider will give you
Imfinzi into your vein through an intravenous (IV) line over 60 minutes.
•
Imfinzi is usually given every 2 weeks.
•
Your healthcare provider will decide how
many treatments you need.
•
Your healthcare provider will test your
blood to check you for certain side effects.
•
If you miss any appointments, call your
healthcare provider as soon as possible to reschedule your appointment.
|
|
What are the possible side effects of
Imfinzi?
Imfinzi can cause serious side effects,
including:
See "What is the most important
information I should know about Imfinzi?"
The most common side effects of Imfinzi
include:
•
feeling tired
•
muscle and/or bone pain
•
constipation
•
decreased appetite
•
nausea
•
swelling
•
urinary tract infection
Tell your healthcare provider if you have
any side effect that bothers you or that does not go away.
These are not all the possible side
effects of Imfinzi. Ask your healthcare provider or pharmacist for more information.
Call your healthcare provider for medical
advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
|
|
General information about the safe and
effective use of Imfinzi.
Medicines are sometimes
prescribed for purposes other than those listed in a Medication Guide. If you
would like more information about Imfinzi, talk with your healthcare
provider. You can ask your healthcare provider for information about Imfinzi
that is written for health professionals.
|
|
What are the ingredients in Imfinzi?
Active ingredient: durvalumab
Inactive ingredients: L-histidine,
L-histidine hydrochloride monohydrate, α,α-trehalose dihydrate, polysorbate
80, water for injection, USP.
|
|
Manufactured for: AstraZeneca
Pharmaceuticals LP, Wilmington, DE 19850
By: AstraZeneca UK Limited
1 Francis Crick Ave.
Cambridge, England CB2 0AA
US License No. 2043
Imfinzi is a trademark of AstraZeneca
group of companies.
For more information, call 1-800-236-9933
or go to www.Imfinzi.com
©AstraZeneca 2017
|
This Medication Guide has been
approved by the U.S. Food and Drug Administration. Issued: 5/2017
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 0310-4500-12
Rx only
Imfinzi™
(durvalumab)
Injection
120 mg/2.4 mL
(50 mg/mL)
For Intravenous Infusion After
Dilution
Single-dose vial. Discard unused portion.
Store at 2° to 8°C (36° to 46°F).
Do not freeze or shake.
Keep vial in original carton to protect from light.
Attention Pharmacist: Dispense the accompanying Medication Guide to each
patient.
Do not use if vial seal is broken or missing.
Must dilute before use.
See prescribing information.
AstraZeneca
PACKAGE/LABEL DISPLAY PANEL
NDC 0310-4611-50
Rx only
Imfinzi™
(durvalumab)
Injection
500 mg/10 mL
(50 mg/mL)
For Intravenous Infusion After
Dilution
Single-dose vial. Discard unused portion.
Store at 2° to 8°C (36° to 46°F).
Do not freeze or shake.
Keep vial in original carton to protect from light.
Attention Pharmacist: Dispense the accompanying Medication Guide to each
patient.
Do not use if vial seal is broken or missing.
Must dilute before use.
See prescribing information.
AstraZeneca
|
Imfinzi durvalumab injection,
solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0310-4500
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
DURVALUMAB (DURVALUMAB)
|
DURVALUMAB
|
120 mg
in 2.4 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
HISTIDINE
|
4.8 mg
in 2.4 mL
|
|
HISTIDINE
MONOHYDROCHLORIDE MONOHYDRATE
|
6.5 mg
in 2.4 mL
|
|
TREHALOSE
DIHYDRATE
|
250 mg
in 2.4 mL
|
|
POLYSORBATE
80
|
0.5 mg
in 2.4 mL
|
|
WATER
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0310-4500-12
|
1 VIAL in 1
CARTON
|
|
|
1
|
|
2.4 mL in 1
VIAL
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
BLA
|
BLA761069
|
05/01/2017
|
|
|
|
Imfinzi durvalumab injection,
solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0310-4611
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
DURVALUMAB (DURVALUMAB)
|
DURVALUMAB
|
500 mg
in 10 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
HISTIDINE
|
20 mg
in 10 mL
|
|
HISTIDINE
MONOHYDROCHLORIDE MONOHYDRATE
|
27 mg
in 10 mL
|
|
TREHALOSE
DIHYDRATE
|
1040 mg
in 10 mL
|
|
POLYSORBATE
80
|
2 mg
in 10 mL
|
|
WATER
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0310-4611-50
|
1 VIAL in 1
CARTON
|
|
|
1
|
|
10 mL in 1 VIAL
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
BLA
|
BLA761069
|
05/01/2017
|
|
|
|
Labeler - AstraZeneca Pharmaceuticals LP (054743190)
|
|
Registrant - AstraZeneca PLC (230790719)
|
Revised:
05/2017
AstraZeneca
Pharmaceuticals LP
