[January 23, 2015] |
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Celgene Receives Positive CHMP Opinion for ABRAXANE® for First-Line Treatment of Patients with Non-Small Cell Lung Cancer
Celgene International Sàrl, a wholly owned subsidiary of Celgene
Corporation (NASDAQ: CELG), today announced that the European Medicines
Agency's (EMA (News - Alert)) Committee for Medicinal Products for Human Use (CHMP) has
adopted a positive opinion for ABRAXANE® (paclitaxel
formulated as albumin-bound nanoparticles, or nab-paclitaxel) in
combination with carboplatin for the first-line treatment of non-small
cell lung cancer in adult patients who are not candidates for
potentially curative surgery and/or radiation therapy.
Lung cancer is the fourth most commonly diagnosed cancer in both men and
women, however it is the leading cause of cancer-related mortality in
Europe. Non-small cell lung cancer (NSCLC) is the most common form of
lung cancer, accounting for 85 to 90% of all cases. The predominant
cause of lung cancer is cigarette smoking, although environmental and
occupational factors also can cause the cancer. Treatment options
generally include systemic chemotherapy or protein kinase inhibitors. In
the most advanced cases, only the symptoms of the disease can be
managed; there is a clear need for innovative new medicines for the
treatment of lung cancer.
"Progress in lung cancer will come first from early diagnosis with
patients presenting promptly with symptoms and second, with new drugs
that are well tolerated and improve on current therapies. Incremental
steps can lead to a meaningful impact on patients and society, given the
frequency and aggressiveness of lung cancer," says Dr. Mary O'Brien,
Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust,
UK. "The positive CHMP opinion for ABRAXANE in combination with
carboplatin for the treatment of adult patients with NSCLC is a
significant step toward bringing a new treatment option to patients in
Europe. The clinical data show patients had a significant positive
response rate to the treatment, combined with an established safety
profile. The therapy has also shown a significant response benefit for a
subset of patients with squamous cell lung cancer, where there have been
limited treatment advances in recent years."
The positive CHMP opinion was based on the results of a multicenter,
randomized, open-label study including 1,052 chemotherapy-naive patients
with Stage IIIb/IV non-small cell lung cancer. The study compared
ABRAXANE in combination with carboplatin versus solvent-based paclitaxel
in combination with carboplatin as first-line treatment in patients with
advanced non-small cell lung cancer. The primary efficacy endpoint,
overall response rate, was significantly higher for patients in the
ABRAXANE/carboplatin arm at 33%, compared with patients in the control
arm, at 25%. The most common adverse reactions
(= 20%) of ABRAXANE in combination with carboplatin for NSCLC were
anaemia, neutropenia, thrombocytopenia, peripheral neuropathy, nausea,
and fatigue.
Tuomo Pätsi, President of Celgene in Europe, the Middle East and Africa
(EMEA), said, "The positive CHMP opinion is the first opportunity for
Celgene to play a role in helping patients with NSCLC have access to an
important treatment option in Europe. The anticipated European
Commission decision would be the third approved indication for ABRAXANE,
underscoring the value of this medicine. We are committed to ensuring
that patients who need ABRAXANE will gain access to it once approved by
the European Commission."
The CHMP reviews applications for all 28 member states in the European
Union (EU), as well as Norway, Liechtenstein and Iceland. The European
Commission, which generally follows the recommendation of the CHMP, is
expected to make its final decision within approximately two months. If
approval is granted, detailed conditions for the use of this product
will be described in the Summary of Product Characteristics (SmPC),
which will be published in the revised European Public Assessment Report
(EPAR).
ABRAXANE is not currently indicated for the treatment of metastatic
NSCLC in the European Union.
About ABRAXANE
ABRAXANE® is an albumin-bound form of paclitaxel that is
manufactured using patented nab® technology.
ABRAXANE is formulated with albumin, a human protein, and is free of
solvents.
ABRAXANE was first approved in January 2005 by the U.S. Food and Drug
Administration (FDA) for the treatment of breast cancer after failure of
combination chemotherapy for metastatic disease or relapse within 6
months of adjuvant chemotherapy. Prior therapy should have included an
anthracycline unless clinically contraindicated. In Europe, ABRAXANE was
approved in January 2008 as monotherapy for the treatment of metastatic
breast cancer in adult patients who have failed first-line treatment for
metastatic disease and for whom standard, anthracycline containing
therapy is not indicated. ABRAXANE is now approved in more than 50
countries for the treatment of metastatic breast cancer.
In October 2012, ABRAXANE was approved by the FDA for the first-line
treatment of locally advanced or metastatic non-small cell lung cancer
(NSCLC), in combination with carboplatin, in patients who are not
candidates for curative surgery or radiation therapy. ABRAXANE is also
approved for the treatment of NSCLC in Argentina, Australia, Chile,
Ecuador, Guatemala, Hong Kong, Japan, New Zealand and Singapore.
In September 2013, the FDA approved ABRAXANE as first-line treatment of
patients with metastatic adenocarcinoma of the pancreas, in combination
with gemcitabine. In December 2013, ABRAXANE in combination with
gemcitabine was approved for first-line treatment of adult patients
with metastatic adenocarcinoma of the pancreas in Europe. ABRAXANE
is also approved for the treatment of metastatic pancreatic cancer in
more than 40 countries.
U.S. Regulatory Information for ABRAXANE
WARNING - NEUTROPENIA
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Do not administer ABRAXANE therapy to patients who have baseline
neutrophil counts of less than 1500 cells/mm3. In order to monitor the
occurrence of bone marrow suppression, primarily neutropenia, which
may be severe and result in infection, it is recommended that frequent
peripheral blood cell counts be performed on all patients receiving
ABRAXANE
-
Note: An albumin form of paclitaxel may substantially affect a drug's
functional properties relative to those of drug in solution. DO NOT
SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS
Neutrophil Counts
-
ABRAXANE should not be used in patients who have baseline neutrophil
counts of <1500 cells/mm3
Hypersensitivity
-
Patients who experience a severe hypersensitivity reaction to ABRAXANE
should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS
Hematologic Effects
-
Bone marrow suppression (primarily neutropenia) is dose-dependent and
a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4
neutropenia occurred in 34% of patients with metastatic breast cancer
(MBC), 47% of patients with non-small cell lung cancer (NSCLC), and
38% of patients with pancreatic cancer
-
Monitor for myelotoxicity by performing complete blood cell counts
frequently, including prior to dosing on Day 1 (for MBC) and Days 1,
8, and 15 (for NSCLC and for pancreatic cancer)
-
Do not administer ABRAXANE to patients with baseline absolute
neutrophil counts (ANC) of less than 1500 cells/mm3
-
In the case of severe neutropenia (<500 cells/mm3 for 7
days or more) during a course of ABRAXANE therapy, reduce the dose of
ABRAXANE in subsequent courses in patients with either MBC or NSCLC
-
In patients with MBC, resume treatment with every-3-week cycles of
ABRAXANE after ANC recovers to a level >1500 cells/mm3
and platelets recover to a level >100,000 cells/mm3
-
In patients with NSCLC, resume treatment if recommended at permanently
reduced doses for both weekly ABRAXANE and every-3-week carboplatin
after ANC recovers to at least 1500 cells/mm3 and
platelet count of at least 100,000 cells/mm3 on Day 1 or to
an ANC of at least 500 cells/mm3 and platelet count of at
least 50,000 cells/mm3 on Days 8 or 15 of the cycle
-
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and
gemcitabine if the ANC is less than 500 cells/mm3 or
platelets are less than 50,000 cells/mm3 and delay
initiation of the next cycle if the ANC is less than 1500 cells/mm3
or platelet count is less than 100,000 cells/mm3 on Day 1
of the cycle. Resume treatment with appropriate dose reduction if
recommended
Nervous System
-
Sensory neuropathy is dose- and schedule-dependent
-
The occurrence of Grade 1 or 2 sensory neuropathy does not generally
require dose modification
-
If = Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment
until resolution to Grade 1 or 2 for MBC or until resolution to
= Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction
for all subsequent courses of ABRAXANE
Sepsis
-
Sepsis occurred in 5% of patients with or without neutropenia who
received ABRAXANE in combination with gemcitabine
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Biliary obstruction or presence of biliary stent were risk factors for
severe or fatal sepsis
-
If a patient becomes febrile (regardless of ANC), initiate treatment
with broad-spectrum antibiotics
-
For febrile neutropenia, interrupt ABRAXANE and gemcitabine until
fever resolves and ANC =1500 cells/mm3, then resume
treatment at reduced dose levels
Pneumonitis
-
Pneumonitis, including some cases that were fatal, occurred in 4% of
patients receiving ABRAXANE in combination with gemcitabine
-
Monitor patients for signs and symptoms and interrupt ABRAXANE and
gemcitabine during evaluation of suspected pneumonitis
-
Permanently discontinue treatment with ABRAXANE and gemcitabine upon
making a diagnosis of pneumonitis
Hypersensitivity
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Severe and sometimes fatal hypersensitivity reactions, including
anaphylactic reactions, have been reported
-
Patients who experience a severe hypersensitivity reaction to ABRAXANE
should not be rechallenged with this drug
Hepatic Impairment
-
Because the exposure and toxicity of paclitaxel can be increased with
hepatic impairment, administration of ABRAXANE in patients with
hepatic impairment should be performed with caution
-
Patients with hepatic impairment may be at an increased risk of
toxicity, particularly from myelosuppression, and should be monitored
for development of profound myelosuppression
-
For MBC and NSCLC, the starting dose should be reduced for patients
with moderate or severe hepatic impairment
-
For pancreatic adenocarcinoma, ABRAXANE is not recommended for
patients with moderate to severe hepatic impairment (total bilirubin
>1.5 x ULN and AST =10 x ULN)
Albumin (Human)
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ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D
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ABRAXANE can cause fetal harm when administered to a pregnant woman
-
If this drug is used during pregnancy, or if the patient becomes
pregnant while receiving this drug, the patient should be apprised of
the potential hazard to the fetus
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Women of childbearing potential should be advised to avoid becoming
pregnant while receiving ABRAXANE
Use in Men
-
Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS
Randomized Metastatic Breast Cancer (MBC) Study
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The most common adverse reactions (=20%) with single-agent use of
ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%,
94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory
neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all
patients 60%, 52%; patients with normal baseline 35%, 30%),
fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia
(any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline
phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%,
<1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%;
severe <1%, 1%) and infections (24%, 20%), respectively
-
Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229
(3%) patients
-
Other adverse reactions of note with the use of ABRAXANE vs paclitaxel
injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid
retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe
<1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%),
hypersensitivity reactions (any 4%, 12%; severe 0%, 2%),
thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis
(<1%, <1%), and injection site reactions (<1%, 1%), respectively.
Dehydration and pyrexia were also reported
-
Renal dysfunction (any 11%, severe 1%) was reported in patients
treated with ABRAXANE (n=229)
-
In all ABRAXANE-treated patients (n=366), ocular/visual disturbances
were reported (any 13%; severe 1%)
-
Severe cardiovascular events possibly related to single-agent ABRAXANE
occurred in approximately 3% of patients and included cardiac
ischemia/infarction, chest pain, cardiac arrest, supraventricular
tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary
emboli, and hypertension
-
Cases of cerebrovascular attacks (strokes) and transient ischemic
attacks have been reported
Non-Small Cell Lung Cancer (NSCLC) Study
-
The most common adverse reactions (=20%) of ABRAXANE in combination
with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia,
peripheral neuropathy, nausea, and fatigue
-
The most common serious adverse reactions of ABRAXANE in combination
with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)
-
The most common adverse reactions resulting in permanent
discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia
(3%), and peripheral neuropathy (1%)
-
The most common adverse reactions resulting in dose reduction of
ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)
-
The most common adverse reactions leading to withholding or delay in
ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and
anemia (16%)
-
The following common (=10% incidence) adverse reactions were observed
at a similar incidence in ABRAXANE plus carboplatin-treated and
paclitaxel injection plus carboplatin-treated patients: alopecia
(56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia
(16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea
(12%), and rash (10%); incidence rates are for the ABRAXANE plus
carboplatin treatment group
-
Adverse reactions with a difference of =2%, Grade 3 or higher, with
combination use of ABRAXANE and carboplatin vs combination use of
paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%),
neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral
neuropathy (3%, 12%), respectively
-
Adverse reactions with a difference of =5%, Grades 1-4, with
combination use of ABRAXANE and carboplatin vs combination use of
paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%),
thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema
peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and
myalgia (10%, 19%), respectively
-
Neutropenia (all grades) was reported in 85% of patients who received
ABRAXANE and carboplatin vs 83% of patients who received paclitaxel
injection and carboplatin
Pancreatic Adenocarcinoma Study
-
Among the most common (=20%) adverse reactions in the phase III study,
those with a =5% higher incidence in the ABRAXANE/gemcitabine group
compared with the gemcitabine group are neutropenia (73%, 58%),
fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%,
48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%,
24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite
(36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
-
Of these most common adverse reactions, those with a =2% higher
incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group
compared with the gemcitabine group, respectively, are neutropenia
(38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea
(6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%),
decreased appetite (5%, 2%), and dehydration (7%, 2%)
-
Thrombocytopenia (all grades) was reported in 74% of patients in the
ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
-
The most common serious adverse reactions of ABRAXANE (with a =1%
higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%),
and vomiting (4%)
-
The most common adverse reactions resulting in permanent
discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue
(4%), and thrombocytopenia (2%)
-
The most common adverse reactions resulting in dose reduction of
ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
-
The most common adverse reactions leading to withholding or delay in
ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue
(8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
-
Other selected adverse reactions with a =5% higher incidence for
all-grade toxicity in the ABRAXANE/gemcitabine group compared to the
gemcitabine group, respectively, are asthenia (19%, 13%), mucositis
(10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%,
7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection
(11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia
(10%, 4%), and depression (12%, 6%)
-
Other selected adverse reactions with a =2% higher incidence for Grade
3-4 toxicity in the ABRAXANE/gemcitabine group compared to the
gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%),
and hypokalemia (4%, 1%)
Postmarketing Experience With ABRAXANE and Other Paclitaxel
Formulations
-
Severe and sometimes fatal hypersensitivity reactions have been
reported with ABRAXANE. The use of ABRAXANE in patients previously
exhibiting hypersensitivity to paclitaxel injection or human albumin
has not been studied
-
There have been reports of congestive heart failure, left ventricular
dysfunction, and atrioventricular block with ABRAXANE, primarily among
individuals with underlying cardiac history or prior exposure to
cardiotoxic drugs
-
There have been reports of extravasation of ABRAXANE. Given the
possibility of extravasation, it is advisable to monitor closely the
ABRAXANE infusion site for possible infiltration during drug
administration
DRUG INTERACTIONS
-
Caution should be exercised when administering ABRAXANE concomitantly
with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS
Nursing Mothers
-
It is not known whether paclitaxel is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants, a decision should be
made to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother
Pediatric
-
The safety and effectiveness of ABRAXANE in pediatric patients have
not been evaluated
Geriatric
-
No toxicities occurred notably more frequently among patients
=65 years of age who received ABRAXANE for MBC
-
Myelosuppression, peripheral neuropathy, and arthralgia were more
frequent in patients =65 years of age treated with ABRAXANE and
carboplatin in NSCLC
-
Diarrhea, decreased appetite, dehydration, and epistaxis were more
frequent in patients 65 years or older compared with patients younger
than 65 years old who received ABRAXANE and gemcitabine in
adenocarcinoma of the pancreas
Renal Impairment
-
There are insufficient data to permit dosage recommendations in
patients with severe renal impairment or end stage renal disease
(estimated creatinine clearance <30 mL/min)
DOSAGE AND ADMINISTRATION
-
Do not administer ABRAXANE to any patient with total bilirubin greater
than 5 x ULN or AST greater than 10 x ULN
-
For MBC and NSCLC, reduce starting dose in patients with moderate to
severe hepatic impairment
-
For adenocarcinoma of the pancreas, do not administer ABRAXANE to
patients who have moderate to severe hepatic impairment
-
Dose reductions or discontinuation may be needed based on severe
hematologic, neurologic, cutaneous, or gastrointestinal toxicity
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Monitor patients closely
Please see full Prescribing Information, including Boxed WARNING.
About Celgene
Celgene International Sàrl, located in Boudry, in the Canton of
Neuchâtel, Switzerland, is a wholly-owned subsidiary and International
Headquarters of Celgene Corporation. Celgene Corporation, headquartered
in Summit, New Jersey, is an integrated global biopharmaceutical company
engaged primarily in the discovery, development and commercialization of
innovative therapies for the treatment of cancer and inflammatory
diseases through gene and protein regulation. For more information,
please visit the Company's website at www.celgene.com.
Follow Celgene on Social Media: @Celgene, Pinterest, LinkedIn and YouTube.
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