Proposal extends application to the treatment
of children and adolescents with chronic phase
Philadelphia-chromosome positive chronic myelogenous leukemia and
to the powder for oral suspension
Bristol-Myers Squibb Company (NYSE:BMY) today announced that the
European Medicines Agency (EMA) validated its grouped Type II
variation/Extension of Application for Sprycel (dasatinib) to treat
children and adolescents aged 1 year to 18 years with chronic phase
Philadelphia chromosome positive chronic myelogenous leukemia (CML)
and to include the powder for oral suspension. Validation of the
application confirms the submission is complete and begins the
EMA’s centralized review process.
“Treatment options for pediatric patients with chronic phase
CML, along with formulations that support the unique demands of
children with cancer continue to be unmet needs,” said Murdo
Gordon, executive vice president and chief commercial officer,
Bristol-Myers Squibb. “Building on our long-standing heritage in
hematology, including the use of Sprycel for more than a decade to
treat adults with certain forms of CML, the validation of this
application supports our commitment to expand options for children
and adolescents with different types of cancer.”
The application includes data from CA180-226 (NCT00777036), an
ongoing Phase 2, open-label, non-randomized trial studying Sprycel
in newly diagnosed chronic phase CML pediatric patients and in
pediatric patients resistant to or intolerant of imatinib. Data
from this study will be presented at the American Society of
Clinical Oncology Annual Meeting 2017 in Chicago on Monday, June
5.
About Sprycel
Sprycel was first approved by the FDA in 2006 for the treatment
of adults with Philadelphia chromosome-positive (Ph+) chronic
myeloid leukemia (CML) in chronic phase (CP) who are resistant or
intolerant to prior therapy including imatinib. At that time,
Sprycel was also approved for adults with Ph+ acute lymphoblastic
leukemia (ALL) who are resistant or intolerant to prior therapy.
Sprycel is approved and marketed worldwide for these indications in
more than 60 countries.
Sprycel is also an FDA-approved treatment for adults with newly
diagnosed CP Ph+ CML (since October 2010). Sprycel received
accelerated FDA approval for this indication. Additional country
approvals for this indication total more than 50.
U.S. FDA-APPROVED INDICATIONS FOR
SPRYCEL®
SPRYCEL® (dasatinib) is indicated for the treatment of
adults with:
- Newly diagnosed adults with
Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia
(CML) in chronic phase.
- Chronic, accelerated, or myeloid or
lymphoid blast phase Ph+ CML with resistance or intolerance to
prior therapy including imatinib.
- Philadelphia chromosome-positive acute
lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to
prior therapy.
IMPORTANT SAFETY
INFORMATION
Myelosuppression
Treatment with SPRYCEL is associated with severe (NCI CTC Grade
3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier
and more frequently in patients with advanced phase CML or Ph+ ALL
than in patients with chronic phase CML. Myelosuppression was
reported in patients with normal baseline laboratory values as well
as in patients with pre-existing laboratory abnormalities.
- In patients with chronic phase CML,
perform complete blood counts (CBCs) every 2 weeks for 12 weeks,
then every 3 months thereafter, or as clinically indicated
- In patients with advanced phase CML or
Ph+ ALL, perform CBCs weekly for the first 2 months and then
monthly thereafter, or as clinically indicated
- Myelosuppression is generally
reversible and usually managed by withholding SPRYCEL temporarily
and/or dose reduction
- In clinical studies, myelosuppression
may have also been managed by discontinuation of study therapy
- Hematopoietic growth factor has been
used in patients with resistant myelosuppression
Bleeding-Related Events
SPRYCEL caused thrombocytopenia in human subjects. In addition,
dasatinib caused platelet dysfunction in vitro. In all CML or
Ph+ ALL clinical studies, ≥grade 3 central nervous system (CNS)
hemorrhages, including fatalities, occurred in <1% of patients
receiving SPRYCEL. Grade 3 or greater gastrointestinal hemorrhage,
including fatalities, occurred in 4% of patients and generally
required treatment interruptions and transfusions. Other cases of
≥grade 3 hemorrhage occurred in 2% of patients.
- Most bleeding events in clinical
studies were associated with severe thrombocytopenia
- Concomitant medications that inhibit
platelet function or anticoagulants may increase the risk of
hemorrhage
Fluid Retention
SPRYCEL may cause fluid retention. After 5 years of follow-up in
the randomized newly diagnosed chronic phase CML study (n=258),
grade 3/4 fluid retention was reported in 5% of patients, including
3% of patients with grade 3/4 pleural effusion. In patients with
newly diagnosed or imatinib resistant or intolerant chronic phase
CML, grade 3/4 fluid retention occurred in 6% of patients treated
with SPRYCEL at the recommended dose (n=548). In patients with
advanced phase CML or Ph+ ALL treated with SPRYCEL at the
recommended dose (n=304), grade 3/4 fluid retention was reported in
8% of patients, including grade 3/4 pleural effusion reported in 7%
of patients.
- Patients who develop symptoms of
pleural effusion or other fluid retention, such as new or worsened
dyspnea on exertion or at rest, pleuritic chest pain, or dry cough
should be evaluated promptly with a chest x-ray or additional
diagnostic imaging as appropriate
- Fluid retention events were typically
managed by supportive care measures that may include diuretics or
short courses of steroids
- Severe pleural effusion may require
thoracentesis and oxygen therapy
- Consider dose reduction or treatment
interruption
Cardiovascular Events
After 5 years of follow-up in the randomized newly diagnosed
chronic phase CML trial (n=258), the following cardiac adverse
events occurred:
- Cardiac ischemic events (3.9% dasatinib
vs 1.6% imatinib), cardiac related fluid retention (8.5% dasatinib
vs 3.9% imatinib), and conduction system abnormalities, most
commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0%
imatinib). Two cases (0.8%) of peripheral arterial occlusive
disease occurred with imatinib and 2 (0.8%) transient ischemic
attacks occurred with dasatinib
Monitor patients for signs or symptoms consistent with cardiac
dysfunction and treat appropriately.
Pulmonary Arterial Hypertension (PAH)
SPRYCEL may increase the risk of developing PAH, which may occur
any time after initiation, including after more than 1 year of
treatment. Manifestations include dyspnea, fatigue, hypoxia, and
fluid retention. PAH may be reversible on discontinuation of
SPRYCEL.
- Evaluate patients for signs and
symptoms of underlying cardiopulmonary disease prior to initiating
SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should
be permanently discontinued
QT Prolongation
In vitro data suggest that dasatinib has the potential to
prolong cardiac ventricular repolarization (QT interval).
- In clinical trials of patients treated
with SPRYCEL at all doses (n=2440), 16 patients (<1%) had
QTc prolongation reported as an adverse reaction. Twenty-two
patients (1%) experienced a QTcF >500 ms
- In 865 patients with leukemia treated
with SPRYCEL in five Phase 2 single-arm studies, the maximum mean
changes in QTcF (90% upper bound CI) from baseline ranged from 7.0
to 13.4 ms
- SPRYCEL may increase the risk of
prolongation of QTc in patients including those with hypokalemia or
hypomagnesemia, patients with congenital long QT syndrome, patients
taking antiarrhythmic medicines or other medicinal products that
lead to QT prolongation, and cumulative high-dose anthracycline
therapy
- Correct hypokalemia or hypomagnesemia
prior to and during SPRYCEL administration
Severe Dermatologic Reactions
Cases of severe mucocutaneous dermatologic reactions, including
Stevens-Johnson syndrome and erythema multiforme, have been
reported in patients treated with SPRYCEL.
- Discontinue permanently in patients who
experience a severe mucocutaneous reaction during treatment if no
other etiology can be identified
Tumor Lysis Syndrome (TLS)
TLS has been reported in patients with resistance to prior
imatinib therapy, primarily in advanced phase disease.
- Due to potential for TLS, maintain
adequate hydration, correct uric acid levels prior to initiating
therapy with SPRYCEL, and monitor electrolyte levels
- Patients with advanced stage disease
and/or high tumor burden may be at increased risk and should be
monitored more frequently
Embryo-Fetal Toxicity
Based on limited human data, SPRYCEL can cause fetal harm when
administered to a pregnant woman. Hydrops fetalis, fetal leukopenia
and fetal thrombocytopenia have been reported with maternal
exposure to SPRYCEL. Transplacental transfer of dasatinib has been
measured in fetal plasma and amniotic fluid at concentrations
comparable to those in maternal plasma.
- Advise females of reproductive
potential to avoid pregnancy, which may include the use of
effective contraception, during treatment with SPRYCEL and for 30
days after the final dose
Lactation
No data are available regarding the presence of dasatinib in
human milk, the effects of the drug on the breastfed infant or the
effects of the drug on milk production. However, dasatinib is
present in the milk of lactating rats.
- Because of the potential for serious
adverse reactions in nursing infants from SPRYCEL, breastfeeding is
not recommended during treatment with SPRYCEL and for 2 weeks after
the final dose
Drug Interactions
SPRYCEL is a CYP3A4 substrate and a weak time-dependent
inhibitor of CYP3A4.
- Drugs that
may increase SPRYCEL plasma concentrations are:
- CYP3A4
inhibitors: Concomitant use of SPRYCEL and drugs that
inhibit CYP3A4 should be avoided. If administration of a potent
CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity
and a SPRYCEL dose reduction should be considered
- Strong CYP3A4
inhibitors (eg, ketoconazole, itraconazole,
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir,
ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL
must be administered with a strong CYP3A4 inhibitor, a dose
decrease or temporary discontinuation should be considered
- Grapefruit juice may also
increase plasma concentrations of SPRYCEL and should be
avoided
- Drugs that
may decrease SPRYCEL plasma concentrations are:
- CYP3A4 inducers: If SPRYCEL must
be administered with a CYP3A4 inducer, a dose increase in SPRYCEL
should be considered
- Strong CYP3A4 inducers (eg,
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,
phenobarbital) should be avoided. Alternative agents with less
enzyme induction potential should be considered. If the dose of
SPRYCEL is increased, the patient should be monitored carefully for
toxicity
- St John’s Wort may decrease
SPRYCEL plasma concentrations unpredictably and should be
avoided
- Antacids may decrease
SPRYCEL drug levels. Simultaneous administration of SPRYCEL and
antacids should be avoided. If antacid therapy is needed, the
antacid dose should be administered at least 2 hours prior to or 2
hours after the dose of SPRYCEL
-
H 2 antagonists/proton pump
inhibitors (eg, famotidine and omeprazole): Long-term
suppression of gastric acid secretion by use of H2 antagonists
or proton pump inhibitors is likely to reduce SPRYCEL exposure.
Therefore, concomitant use of H2 antagonists or proton pump
inhibitors with SPRYCEL is not recommended
- Drugs that may have their plasma
concentration altered by SPRYCEL are:
- CYP3A4 substrates (eg,
simvastatin) with a narrow therapeutic index should be administered
with caution in patients receiving SPRYCEL
Adverse Reactions
The safety data reflects exposure to SPRYCEL at all doses tested
in clinical studies including 324 patients with newly diagnosed
chronic phase CML and 2388 patients with imatinib resistant or
intolerant chronic or advanced phase CML or Ph+ ALL.
The median duration of therapy in all 2712 SPRYCEL-treated
patients was 19.2 months (range 0–93.2 months). Median duration of
therapy in:
- 1618 patients with chronic phase CML
was 29 months (range 0–92.9 months)
- Median duration for 324 patients in the
newly diagnosed chronic phase CML trial was approximately 60
months
- 1094 patients with advanced phase CML
or Ph+ ALL was 6.2 months (range 0–93.2 months)
In the newly diagnosed chronic phase CML trial, after a minimum
of 60 months of follow-up, the cumulative discontinuation rate for
258 patients was 39%.
In the overall population of 2712 SPRYCEL-treated patients, 88%
of patients experienced adverse reactions at some time and 19%
experienced adverse reactions leading to treatment
discontinuation.
Among the 1618 SPRYCEL-treated patients with chronic phase CML,
drug-related adverse events leading to discontinuation were
reported in 329 (20.3%) patients.
- In the newly diagnosed chronic phase
CML trial, drug was discontinued for adverse reactions in 16% of
SPRYCEL-treated patients with a minimum of 60 months of
follow-up
Among the 1094 SPRYCEL-treated patients with advanced phase CML
or Ph+ ALL, drug-related adverse events leading to discontinuation
were reported in 191 (17.5%) patients. Patients ≥65 years are more
likely to experience the commonly reported adverse reactions of
fatigue, pleural effusion, diarrhea, dyspnea, cough, lower
gastrointestinal hemorrhage, and appetite disturbance, and more
likely to experience the less frequently reported adverse reactions
of abdominal distention, dizziness, pericardial effusion,
congestive heart failure, hypertension, pulmonary edema and weight
decrease, and should be monitored closely.
- In newly diagnosed chronic phase CML
patients:
- Drug-related serious adverse events
(SAEs) were reported for 16.7% of SPRYCEL-treated patients. Serious
adverse reactions reported in ≥5% of patients included pleural
effusion (5%)
- The most common adverse reactions
(≥15%) included myelosuppression, fluid retention, and
diarrhea
- Grade 3/4 laboratory abnormalities
included neutropenia (29%), thrombocytopenia (22%), anemia (13%),
hypophosphatemia (7%), hypocalcemia (4%), elevated bilirubin (1%),
and elevated creatinine (1%)
- In patients resistant or intolerant to
prior imatinib therapy:
- Drug-related SAEs were reported for
26.1% of SPRYCEL-treated patients treated at the recommended dose
of 100 mg once daily in the randomized dose-optimization trial of
patients with chronic phase CML resistant or intolerant to prior
imatinib therapy. Serious adverse reactions reported in ≥5% of
patients included pleural effusion (10%)
- The most common adverse reactions
(≥15%) included myelosuppression, fluid retention events, diarrhea,
headache, fatigue, dyspnea, skin rash, nausea, hemorrhage and
musculoskeletal pain
- Grade 3/4 hematologic laboratory
abnormalities in chronic phase CML patients resistant or intolerant
to prior imatinib therapy who received SPRYCEL 100 mg once daily
with a minimum follow up of 60 months included neutropenia (36%),
thrombocytopenia (24%), and anemia (13%). Other grade 3/4
laboratory abnormalities included: hypophosphatemia (10%), and
hypokalemia (2%)
- Among chronic phase CML patients with
resistance or intolerance to prior imatinib therapy, cumulative
grade 3/4 cytopenias were similar at 2 and 5 years including:
neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia
(13% vs 13%)
- Grade 3/4 elevations of transaminases
or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and
hypophosphatemia were reported in patients with all phases of CML
- Elevations in transaminases or
bilirubin were usually managed with dose reduction or
interruption
- Patients developing Grade 3/4
hypocalcemia during the course of SPRYCEL therapy often had
recovery with oral calcium supplementation
Please see the full Prescribing Information
for SPRYCEL.
Please see the US full Prescribing
Information here.
About Bristol-Myers
Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol-Myers Squibb, visit us at BMS.com or
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Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee
that Sprycel will receive regulatory approval for an additional
indication described herein. Forward-looking statements in this
press release should be evaluated together with the many
uncertainties that affect Bristol-Myers Squibb's business,
particularly those identified in the cautionary factors discussion
in Bristol-Myers Squibb's Annual Report on Form 10-K for the year
ended December 31, 2016 in our Quarterly Reports on Form 10-Q and
our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement,
whether as a result of new information, future events or
otherwise.
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Bristol-Myers SquibbMedia:Audrey Abernathy,
919-605-4521audrey.abernathy@bms.comorInvestors:Tim Power,
609-252-7509timothy.power@bms.comorBill Szablewski,
609-252-5894william.szablewski@bms.com
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