SUMMIT, N.J, - Sunday, July 21st 2013 [ME NewsWire]
(BUSINESS
WIRE) Celgene Corporation (NASDAQ: CELG) today announced that after
consultation with the U.S. Food and Drug Administration (FDA) Celgene
will discontinue treatment with REVLIMID® (lenalidomide) in the
open-label, phase III ORIGIN® trial, which enrolled 450 patients in over
100 sites in 26 countries. An imbalance was observed in the number of
deaths in patients treated with lenalidomide versus patients treated
with chlorambucil.
The FDA placed the ORIGIN study on clinical
hold on July 12, 2013, with the discontinuation of lenalidomide
treatment. All clinical investigators in ongoing chronic lymphocytic
leukemia studies using lenalidomide will be officially advised of this
action and instructed to inform their patients accordingly.
REVLIMID is not approved as a treatment for patients with chronic lymphocytic leukemia.
The
ORIGIN study was designed to evaluate the efficacy and safety of
lenalidomide versus chlorambucil as single agent in elderly patients ≥
65 years of age with B-cell chronic lymphocytic leukemia and with
comorbidities that precluded treatment with more aggressive standard
chemo-immunotherapies, including fludarabine and bendamustine containing
regimens. The majority of patients presented with multiple
comorbidities, such as diabetes, congestive heart failure, renal
impairment and elevated bilirubin count.
Based on an imbalance in
deaths, specifically 34 deaths out of 210 patients in the lenalidomide
arm compared to 18 deaths out of 211 patients in the chlorambucil arm,
FDA placed the study on clinical hold. No specific causality for this
imbalance has been identified to date.
Results from the CLL-008 study will be presented at an upcoming medical conference.
All
other Celgene-sponsored chronic lymphocytic leukemia clinical trials
with lenalidomide are continuing in accordance with their respective
protocols.
About REVLIMID®
REVLIMID is approved in
combination with dexamethasone for the treatment of patients with
multiple myeloma who have received at least one prior therapy, in nearly
70 countries, encompassing Europe, the Americas, the Middle-East and
Asia, and in combination with dexamethasone for the treatment of
patients whose disease has progressed after one therapy in Australia and
New Zealand.
REVLIMID is approved in the United States, Canada,
Switzerland, Australia, New Zealand and several Latin American
countries, as well as Malaysia, for transfusion-dependent anaemia due to
low- or intermediate-1-risk MDS associated with a deletion 5q
cytogenetic abnormality with or without additional cytogenetic
abnormalities and in Europe for the treatment of patients with
transfusion-dependent anemia due to low- or intermediate-1-risk
myelodysplastic syndromes associated with an isolated deletion 5q
cytogenetic abnormality when other therapeutic options are insufficient
or inadequate.
REVLIMID is approved in the United States for the
treatment of patients with mantle cell lymphoma (MCL) whose disease has
relapsed or progressed after two prior therapies, one of which included
bortezomib.
U.S. Regulatory Information for Revlimid
REVLIMID®
(lenalidomide) in combination with dexamethasone is indicated for the
treatment of patients with multiple myeloma (MM) who have received at
least one prior therapy
REVLIMID® (lenalidomide) is indicated for
the treatment of patients with transfusion-dependent anemia due to low-
or intermediate-1–risk myelodysplastic syndromes (MDS) associated with a
deletion 5q cytogenetic abnormality with or without additional
cytogenetic abnormalities
REVLIMID® (lenalidomide) is indicated
for the treatment of patients with mantle cell lymphoma (MCL) whose
disease has relapsed or progressed after two prior therapies, one of
which included bortezomib
Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM
Embryo-Fetal Toxicity
Do
not use REVLIMID during pregnancy. Lenalidomide, a thalidomide
analogue, caused limb abnormalities in a developmental monkey study.
Thalidomide is a known human teratogen that causes severe
life-threatening human birth defects. If lenalidomide is used during
pregnancy, it may cause birth defects or embryo-fetal death. In females
of reproductive potential, obtain 2 negative pregnancy tests before
starting REVLIMID treatment. Females of reproductive potential must use 2
forms of contraception or continuously abstain from heterosexual sex
during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal
exposure to lenalidomide, REVLIMID is only available through a
restricted distribution program, the REVLIMID REMS™ program (formerly
known as the “RevAssist®”program).
Information about the REVLIMID
REMS™ Program is available at www.celgeneriskmanagement.com or by
calling the manufacturer’s toll-free number 1-888-423-5436.
Hematologic Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID
can cause significant neutropenia and thrombocytopenia. Eighty percent
of patients with del 5q MDS had to have a dose delay/reduction during
the major study. Thirty-four percent of patients had to have a second
dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80%
of patients enrolled in the study. Patients on therapy for del 5q MDS
should have their complete blood counts monitored weekly for the first 8
weeks of therapy and at least monthly thereafter. Patients may require
dose interruption and/or reduction. Patients may require use of blood
product support and/or growth factors.
Venous Thromboembolism
REVLIMID
has demonstrated a significantly increased risk of deep vein thrombosis
(DVT) and pulmonary embolism (PE) in patients with MM who were treated
with REVLIMID and dexamethasone therapy. Patients and physicians are
advised to be observant for the signs and symptoms of thromboembolism.
Patients should be instructed to seek medical care if they develop
symptoms such as shortness of breath, chest pain, or arm or leg
swelling. It is not known whether prophylactic anticoagulation or
antiplatelet therapy prescribed in conjunction with REVLIMID may lessen
the potential for venous thromboembolism. The decision to take
prophylactic measures should be done carefully after an assessment of an
individual patient’s underlying risk factors.
CONTRAINDICATIONS
Pregnancy:
REVLIMID can cause fetal harm when administered to a pregnant female.
Lenalidomide is contraindicated in females who are pregnant. If this
drug is used during pregnancy or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard
to the fetus
Allergic Reactions:
REVLIMID is
contraindicated in patients who have demonstrated hypersensitivity
(e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis)
to lenalidomide
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity:
REVLIMID is an analogue of thalidomide, a known human teratogen that
causes life-threatening human birth defects or embryo-fetal death. An
embryo-fetal development study in monkeys indicates that lenalidomide
produced malformations in the offspring of female monkeys who received
the drug during pregnancy, similar to birth defects observed in humans
following exposure to thalidomide during pregnancy
Females of
Reproductive Potential: Must avoid pregnancy for at least 4 weeks before
beginning REVLIMID therapy, during therapy, during dose interruptions
and for at least 4 weeks after completing therapy. Must commit either to
abstain continuously from heterosexual sexual intercourse or to use two
methods of reliable birth control beginning 4 weeks prior to initiating
treatment with REVLIMID, during therapy, during dose interruptions and
continuing for 4 weeks following discontinuation of REVLIMID therapy.
Must obtain 2 negative pregnancy tests prior to initiating therapy
Males: Lenalidomide is present in the semen of patients receiving the
drug. Males must always use a latex or synthetic condom during any
sexual contact with females of reproductive potential while taking
REVLIMID and for up to 28 days after discontinuing REVLIMID, even if
they have undergone a successful vasectomy. Male patients taking
REVLIMID must not donate sperm
Blood Donation: Patients must not
donate blood during treatment with REVLIMID and for 1 month following
discontinuation of the drug because the blood might be given to a
pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS™ Program
Because
of embryo-fetal risk, REVLIMID is available only through a restricted
program under a Risk Evaluation and Mitigation Strategy (REMS) the
REVLIMID REMS Program (formerly known as the “RevAssist®” Program).
Prescribers and pharmacies must be certified with the program and
patients must sign an agreement form and comply with the requirements.
Further information about the REVLIMID REMS program is available at
www.celgeneriskmanagement.com or by telephone at 1-888-423-5436
Hematologic
Toxicity: REVLIMID can cause significant neutropenia and
thrombocytopenia. MM: Patients taking REVLIMID for MM should have their
complete blood counts monitored every 2 weeks for the first 12 weeks and
then monthly thereafter. In the pooled MM trials Grade 3 and 4
hematologic toxicities were more frequent in patients treated with the
combination of REVLIMID and dexamethasone than in patients treated with
dexamethasone alone. MCL: Patients taking REVLIMID for MCL should have
their complete blood counts monitored weekly for the first cycle (28
days), every 2 weeks during cycles 2-4, and then monthly thereafter. In
the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the
patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the
patients. Patients may require dose interruption and/or dose reduction
Venous
Thromboembolism: Venous thromboembolic events (predominantly deep
venous thrombosis and pulmonary embolism) have occurred in patients with
MM treated with lenalidomide combination therapy and patients with MDS
or MCL treated with lenalidomide monotherapy. It is not known whether
prophylactic anticoagulation or antiplatelet therapy prescribed in
conjunction with REVLIMID may lessen the potential for venous
thromboembolism. The decision to take prophylactic measures should be
done carefully after assessment of the individual patient’s underlying
risk factors
Allergic Reactions: Angioedema and serious
dermatologic reactions including Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN) have been reported. These events can be
fatal. Patients with a prior history of Grade 4 rash associated with
thalidomide treatment should not receive REVLIMID. REVLIMID interruption
or discontinuation should be considered for Grade 2-3 skin rash.
REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative
or bullous rash, or if SJS or TEN is suspected and should not be resumed
following discontinuation for these reactions. REVLIMID capsules
contain lactose. Risk-benefit of REVLIMID treatment should be evaluated
in patients with lactose intolerance
Tumor Lysis Syndrome: Fatal
instances of tumor lysis syndrome (TLS) have been reported during
treatment with lenalidomide. The patients at risk of TLS are those with
high tumor burden prior to treatment. These patients should be monitored
closely and appropriate precautions taken
Tumor Flare Reaction:
Tumor flare reaction (TFR) has occurred during investigational use of
lenalidomide for chronic lymphocytic leukemia (CLL) and lymphoma, and is
characterized by tender lymph node swelling, low grade fever, pain and
rash. Treatment of CLL with lenalidomide outside of a well-monitored
clinical trial is discouraged
Monitoring and evaluation for TFR
is recommended in patients with MCL. Tumor flare may mimic the
progression of disease (PD). In patients with Grade 3 or 4 TFR, it is
recommended to withhold treatment with lenalidomide until TFR resolves
to ≤ Grade 1. In the MCL trial, approximately 10% of subjects
experienced TFR; all reports were Grade 1 or 2 in severity. All of the
events occurred in cycle 1 and one patient developed TFR again in cycle
11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR
without interruption or modification, at the physician’s discretion.
Patients with Grade 1 or 2 TFR may also be treated with corticosteroids,
non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic
analgesics for management of TFR symptoms. Patients with Grade 3 or 4
TFR may be treated for management of symptoms per the guidance for
treatment of Grade 1 and 2 TFR
Hepatotoxicity: Hepatic failure,
including fatal cases, has occurred in patients treated with
lenalidomide in combination with dexamethasone. The mechanism of
drug-induced hepatotoxicity is unknown. Pre-existing viral liver
disease, elevated baseline liver enzymes, and concomitant medications
may be risk factors. Monitor liver enzymes periodically. Stop Revlimid
upon elevation of liver enzymes. After return to baseline values,
treatment at a lower dose may be considered
Second Primary
Malignancies: Patients with MM treated with lenalidomide in studies
including melphalan and stem cell transplantation had a higher incidence
of second primary malignancies, particularly acute myelogenous leukemia
(AML) and Hodgkin lymphoma, compared to patients in the control arms
who received similar therapy but did not receive lenalidomide. Monitor
patients for the development of second malignancies. Take into account
both the potential benefit of lenalidomide and the risk of second
primary malignancies when considering treatment with lenalidomide
ADVERSE REACTIONS
Multiple Myeloma
In the REVLIMID/dexamethasone treatment group, 269 patients (76%)
underwent at least one dose interruption with or without a dose
reduction of REVLIMID compared to 199 patients (57%) in the
placebo/dexamethasone treatment group
Of these patients who had
one dose interruption with or without a dose reduction, 76% (269/353) vs
57% (199/350), 50% in the REVLIMID/dexamethasone treatment group
underwent at least one additional dose interruption with or without a
dose reduction compared to 21% in the placebo/dexamethasone treatment
group
Most adverse events and Grade 3/4 adverse events were more
frequent in MM patients who received the combination of
REVLIMID/dexamethasone compared to placebo/dexamethasone
Grade 3/4 neutropenia occurred in 33.4% vs 3.4%; 2.3% experienced Grade 3/4 febrile neutropenia vs 0%
Deep vein thrombosis (DVT) was reported as a serious adverse drug
reaction (7.4%) or Grade 3/4 (8.2%) compared to 3.1% and 3.4%.
Discontinuations due to DVT were reported at comparable rates between
groups
Pulmonary embolism (PE) was reported as a serious adverse
drug reaction (3.7%) or Grade 3/4 (4.0%) compared to 0.9% and 0.9%.
Discontinuations due to PE were reported at comparable rates between
groups
Adverse reactions reported in ≥15% of MM patients
(REVLIMID/dexamethasone vs dexamethasone/placebo): fatigue (44% vs 42%),
neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs
27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs
23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26%
vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24%
vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash
(21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%),
nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16%
vs 10%), and dysgeusia (15% vs 10%)
Myelodysplastic Syndromes
Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were
the most frequently reported adverse events observed in the del 5q MDS
population
Grade 3 and 4 adverse events reported in ≥ 5% of
patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%),
pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%),
dyspnea (5%), and back pain (5%)
Other adverse events reported in
≥15% of del 5q MDS patients (REVLIMID): diarrhea (49%), pruritus (42%),
rash (36%), fatigue (31%), constipation (24%), nausea (24%),
nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%),
peripheral edema (20%), cough (20%), dizziness (20%), headache (20%),
muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%),
asthenia (15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma
Grade 3 and 4 adverse events reported in ≥5% of patients treated with
REVLIMID in the MCL trial (N=134) included neutropenia (43%),
thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%),
fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
Serious adverse events reported in ≥2 patients treated with REVLIMID
monotherapy for MCL included chronic obstructive pulmonary disease,
clostridium difficile colitis, sepsis, basal cell carcinoma, and
supraventricular tachycardia
Adverse events reported in ≥15% of
patients treated with REVLIMID in the MCL trial included neutropenia
(49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea
(31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea
(18%), pruritus (17%), peripheral edema (16%), constipation (16%), and
leukopenia (15%)
Adverse events occurring in patients treated
with REVLIMID in the MCL trial resulted in at least one dose
interruption in 76 (57%) patients, at least one dose reduction in 51
(38%) patients, and discontinuation of treatment in 26 (19%) patients
DRUG INTERACTIONS
Periodic
monitoring of digoxin plasma levels, in accordance with clinical
judgment and based on standard clinical practice in patients receiving
this medication, is recommended during administration of REVLIMID. It is
not known whether there is an interaction between dexamethasone and
warfarin. Close monitoring of PT and INR is recommended in MM patients
taking concomitant warfarin. Erythropoietic agents, or other agents,
that may increase the risk of thrombosis, such as estrogen containing
therapies, should be used with caution in MM patients receiving
lenalidomide with dexamethasone
USE IN SPECIFIC POPULATIONS
Pregnancy:
If pregnancy does occur during treatment, immediately discontinue the
drug. Under these conditions, refer patient to an
obstetrician/gynecologist experienced in reproductive toxicity for
further evaluation and counseling. Any suspected fetal exposure to
REVLIMID must be reported to the FDA via the MedWatch program at
1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436
Nursing
Mothers: It is not known whether REVLIMID is excreted in human milk.
Because many drugs are excreted in human milk and because of the
potential for adverse reactions in nursing infants, a decision should be
made whether to discontinue nursing or the drug, taking into account
the importance of the drug to the mother
Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established
Geriatric
Use: Since elderly patients are more likely to have decreased renal
function, care should be taken in dose selection. Monitor renal function
Renal
Impairment: Since REVLIMID is primarily excreted unchanged by the
kidney, adjustments to the starting dose of REVLIMID are recommended to
provide appropriate drug exposure in patients with moderate (CLcr 30-60
mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients
on dialysis
Please see full Prescribing Information, including
Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE
REACTIONS.
About Celgene
Celgene Corporation,
headquartered in Summit, New Jersey, is an integrated global
pharmaceutical 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.
Forward-Looking Statements
This press
release contains forward-looking statements, which are generally
statements that are not historical facts. Forward-looking statements can
be identified by the words "expects," "anticipates," "believes,"
"intends," "estimates," "plans," "will," “outlook” and similar
expressions. Forward-looking statements are based on management’s
current plans, estimates, assumptions and projections, and speak only as
of the date they are made. We undertake no obligation to update any
forward-looking statement in light of new information or future events,
except as otherwise required by law. Forward-looking statements involve
inherent risks and uncertainties, most of which are difficult to predict
and are generally beyond our control. Actual results or outcomes may
differ materially from those implied by the forward-looking statements
as a result of the impact of a number of factors, many of which are
discussed in more detail in our Annual Report on Form 10-K and our other
reports filed with the Securities and Exchange Commission.
Contacts
For Celgene:
Investors:
908-673-9628
investors@celgene.com
Media:
908-673-2275
media@celgene.com
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