Data Presented Today at the 56th
Annual American Society of Hematology (ASH) Meeting
Bristol-Myers Squibb Company (NYSE:BMY) and Pfizer Inc.
(NYSE:PFE) today announced results of the first human study
evaluating the reversal of the anticoagulant effect of Eliquis
(apixaban) by 4-factor prothrombin complex concentrates (PCCs) in
healthy subjects. The study results demonstrated that both PCCs,
Sanquin’s Cofact (a heparin-free formulation) and CSL Behring’s
Beriplex P/N (a formulation containing heparin) reversed the
steady-state pharmacodynamic effects of Eliquis in several
coagulation assessments, including endogenous thrombin potential
(ETP). The full data will be presented today during the
Antithrombotic Therapy: Anticoagulant Therapy session at the 56th
annual meeting of the American Society of Hematology (ASH) in San
Francisco, CA.
“The Bristol-Myers Squibb and Pfizer alliance remains committed
to delivering important treatment options to patients and
physicians and is pleased with the positive results of this study
investigating the potential use of these PCCs to reverse the
anticoagulant effect of Eliquis,” said Steven Romano, MD, senior
vice president and head, Medicines Development Group, Pfizer Global
Innovative Pharmaceutical Business. “These results support further
evaluation of the use of PCCs in Eliquis-treated subjects.”
“Throughout our collaboration with Pfizer, the alliance has been
dedicated to further investigating the use and application of
Eliquis,” said Douglas Manion, MD, head of specialty development,
Bristol-Myers Squibb. “We are pleased with the positive results of
this study and look forward to further exploration of prothrombin
complex concentrates.”
Eliquis is a novel oral anticoagulant that specifically inhibits
Factor Xa. This study evaluated the effect of two non-activated
4-factor PCCs, Cofact and Beriplex P/N, on Eliquis pharmacodynamics
and pharmacokinetics in healthy subjects. Cofact and Beriplex P/N
are used to stop severe bleeding in patients taking vitamin K
antagonists, such as warfarin, or with a blood clotting factor
deficiency. Currently there are no approved reversal agents for
Eliquis or other direct Factor Xa inhibitors.
The study was an open label, randomized, placebo-controlled,
three-period crossover study in 15 healthy, adult subjects (mean
age 33±7 years). Within each period, subjects received Eliquis 10
mg twice daily. On day four (after steady-state was achieved),
three hours after Eliquis administration, subjects received a
30-minute infusion of 4-factor PCCs, either 50 IU/kg Cofact or
Beriplex P/N, or an equivalent volume of saline solution. The
effect of Cofact and Beriplex P/N on the pharmacodynamics of
Eliquis was based upon changes in endogenous thrombin potential, a
measure of thrombin-mediated coagulation. Treatment periods were
separated by an 11-day washout, after which the alternate treatment
was administered.
The mean Eliquis pharmacokinetic profiles were consistent across
all treatment groups and were not affected by PCC administration.
Following completion of the 30-minute Cofact infusion, the effect
of Eliquis on ETP was significantly reduced compared to placebo (p
<0.001). Following completion of the 30-minute Beriplex P/N
infusion, the effect of Eliquis on ETP was reduced; however, this
did not achieve statistical significance (p >0.05). Mean ETP was
comparable to the day four Eliquis pre-dose value (steady-state
trough Eliquis concentration) at the end of the Cofact infusion and
30 minutes after completing the Beriplex P/N infusion. Mean ETP was
within the baseline value (Eliquis naïve) within 5.5 hours after
completing the infusion for both PCCs.
In this study, no serious adverse events, bleeding-related
events or signs of thrombosis were reported with Eliquis
administration with or without PCC treatment.
Overall, these data demonstrate that Cofact and Beriplex P/N
reversed the steady-state pharmacodynamic effects of Eliquis as
measured by ETP and support further evaluation of PCCs in the
management of patients treated with Eliquis who require reversal of
its anticoagulant effect.
About Eliquis
Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By
inhibiting Factor Xa, a key blood clotting protein, Eliquis
decreases thrombin generation and blood clot formation. Eliquis is
approved for multiple indications in the U.S. based on efficacy and
safety data, including results from seven Phase 3 clinical trials.
Eliquis is indicated to reduce the risk of stroke and systemic
embolism in patients with nonvalvular atrial fibrillation; for the
prophylaxis of deep vein thrombosis (DVT), which may lead to
pulmonary embolism (PE), in patients who have undergone hip or knee
replacement surgery; for the treatment of DVT and PE; and to reduce
the risk of recurrent DVT and PE following initial therapy.
ELIQUIS Indications and Important Safety Information
Indications
ELIQUIS is indicated to reduce the risk of stroke and systemic
embolism in patients with nonvalvular atrial fibrillation.
ELIQUIS is indicated for the prophylaxis of deep vein thrombosis
(DVT), which may lead to pulmonary embolism (PE), in patients who
have undergone hip or knee replacement surgery.
ELIQUIS is indicated for the treatment of DVT and PE, and to
reduce the risk of recurrent DVT and PE following initial
therapy.
Important Safety Information
WARNING: (A) PREMATURE DISCONTINUATION
OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B)
SPINAL/EPIDURAL HEMATOMA
(A) Premature discontinuation of any
oral anticoagulant, including ELIQUIS, increases the risk of
thrombotic events. If anticoagulation with ELIQUIS is discontinued
for a reason other than pathological bleeding or completion of a
course of therapy, consider coverage with another
anticoagulant.
(B) Epidural or spinal hematomas may
occur in patients treated with ELIQUIS who are receiving neuraxial
anesthesia or undergoing spinal puncture. These hematomas may
result in long-term or permanent paralysis. Consider these risks
when scheduling patients for spinal procedures. Factors that can
increase the risk of developing epidural or spinal hematomas in
these patients include:
• use of indwelling epidural
catheters
• concomitant use of other drugs that
affect hemostasis, such as nonsteroidal anti-inflammatory drugs
(NSAIDs), platelet inhibitors, other anticoagulants
• a history of traumatic or repeated
epidural or spinal punctures
• a history of spinal deformity or
spinal surgery
• optimal timing between the
administration of ELIQUIS and neuraxial procedures is not
known
Monitor patients frequently for signs
and symptoms of neurological impairment. If neurological compromise
is noted, urgent treatment is necessary.
Consider the benefits and risks before
neuraxial intervention in patients anticoagulated or to be
anticoagulated.
CONTRAINDICATIONS
- Active pathological bleeding
- Severe hypersensitivity reaction to
ELIQUIS (e.g., anaphylactic reactions)
WARNINGS AND PRECAUTIONS
- Increased Risk of Thrombotic Events
after Premature Discontinuation: Premature discontinuation of
any oral anticoagulant, including ELIQUIS, in the absence of
adequate alternative anticoagulation increases the risk of
thrombotic events. An increased rate of stroke was observed during
the transition from ELIQUIS to warfarin in clinical trials in
atrial fibrillation patients. If ELIQUIS is discontinued for a
reason other than pathological bleeding or completion of a course
of therapy, consider coverage with another anticoagulant.
- Bleeding Risk: ELIQUIS increases
the risk of bleeding and can cause serious, potentially fatal
bleeding.
- Concomitant use of drugs affecting
hemostasis increases the risk of bleeding including aspirin and
other anti-platelet agents, other anticoagulants, heparin,
thrombolytic agents, SSRIs, SNRIs, and NSAIDs.
- Advise patients of signs and symptoms
of blood loss and to report them immediately or go to an emergency
room. Discontinue ELIQUIS in patients with active pathological
hemorrhage.
- There is no established way to reverse
the anticoagulant effect of apixaban, which can be expected to
persist for at least 24 hours after the last dose (i.e., about two
half-lives). A specific antidote for ELIQUIS is not available.
- Spinal/Epidural Anesthesia or
Puncture: Patients treated with Eliquis undergoing
spinal/epidural anesthesia or puncture may develop an epidural or
spinal hematoma which can result in long-term or permanent
paralysis.The risk of these events may be increased by the
postoperative use of indwelling epidural catheters or the
concomitant use of medicinal products affecting hemostasis.
Indwelling epidural or intrathecal catheters should not be removed
earlier than 24 hours after the last administration of ELIQUIS. The
next dose of ELIQUIS should not be administered earlier than 5
hours after the removal of the catheter. The risk may also be
increased by traumatic or repeated epidural or spinal puncture. If
traumatic puncture occurs, delay the administration of ELIQUIS for
48 hours.Monitor patients frequently and if neurological compromise
is noted, urgent diagnosis and treatment is necessary. Physicians
should consider the potential benefit versus the risk of neuraxial
intervention in Eliquis patients.
- Prosthetic Heart Valves: The
safety and efficacy of ELIQUIS have not been studied in patients
with prosthetic heart valves and is not recommended in these
patients.
- Acute PE in Hemodynamically Unstable
Patients or Patients who Require Thrombolysis or Pulmonary
Embolectomy: Initiation of ELIQUIS is not recommended as an
alternative to unfractionated heparin for the initial treatment of
patients with PE who present with hemodynamic instability or who
may receive thrombolysis or pulmonary embolectomy.
ADVERSE REACTIONS
- The most common and most serious
adverse reactions reported with ELIQUIS were related to
bleeding.
TEMPORARY INTERRUPTION FOR SURGERY AND OTHER
INTERVENTIONS
- ELIQUIS should be discontinued at least
48 hours prior to elective surgery or invasive procedures with a
moderate or high risk of unacceptable or clinically significant
bleeding. ELIQUIS should be discontinued at least 24 hours prior to
elective surgery or invasive procedures with a low risk of bleeding
or where the bleeding would be noncritical in location and easily
controlled. Bridging anticoagulation during the 24 to 48 hours
after stopping ELIQUIS and prior to the intervention is not
generally required. ELIQUIS should be restarted after the surgical
or other procedures as soon as adequate hemostasis has been
established.
DRUG INTERACTIONS
- Strong Dual Inhibitors of CYP3A4 and
P-gp: Inhibitors of CYP3A4 and P-gp increase exposure to
apixaban and increase the risk of bleeding. For patients receiving
ELIQUIS doses greater than 2.5 mg twice daily, the dose of ELIQUIS
should be decreased by 50% when it is coadministered with drugs
that are strong dual inhibitors of CYP3A4 and P-gp (e.g.,
ketoconazole, itraconazole, ritonavir, or clarithromycin). For
patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid
coadministration with strong dual inhibitors of CYP3A4 and
P-gp.
- Strong Dual Inducers of CYP3A4 and
P-gp: Avoid concomitant use of ELIQUIS with strong dual
inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine,
phenytoin, St. John’s wort) because such drugs will decrease
exposure to apixaban and increase the risk of stroke and other
thromboembolic events.
- Anticoagulants and Antiplatelet
Agents: Coadministration of antiplatelet agents, fibrinolytics,
heparin, aspirin, and chronic NSAID use increases the risk of
bleeding. APPRAISE-2, a placebo-controlled clinical trial of
apixaban in high-risk post-acute coronary syndrome patients treated
with aspirin or the combination of aspirin and clopidogrel, was
terminated early due to a higher rate of bleeding with apixaban
compared to placebo.
PREGNANCY CATEGORY B
- There are no adequate and
well-controlled studies of ELIQUIS in pregnant women. Treatment is
likely to increase the risk of hemorrhage during pregnancy and
delivery. ELIQUIS should be used during pregnancy only if the
potential benefit outweighs the potential risk to the mother and
fetus.
Please see full Prescribing Information, including BOXED
WARNINGS and Medication Guide, available at
www.bms.com.
About the Bristol-Myers Squibb/Pfizer Collaboration
In 2007, Pfizer and Bristol-Myers Squibb entered into a
worldwide collaboration to develop and commercialize apixaban, an
oral anticoagulant discovered by Bristol-Myers Squibb. This global
alliance combines Bristol-Myers Squibb's long-standing strengths in
cardiovascular drug development and commercialization with Pfizer’s
global scale and expertise in this field.
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, please visit www.bms.com or follow us on Twitter at
http://twitter.com/bmsnews.
About Pfizer Inc.: Working together for a healthier
world®
At Pfizer, we apply science and our global resources to bring
therapies to people that extend and significantly improve their
lives. We strive to set the standard for quality, safety and value
in the discovery, development and manufacture of health care
products. Our global portfolio includes medicines and vaccines as
well as many of the world's best-known consumer health care
products. Every day, Pfizer colleagues work across developed and
emerging markets to advance wellness, prevention, treatments and
cures that challenge the most feared diseases of our time.
Consistent with our responsibility as one of the world's premier
innovative biopharmaceutical companies, we collaborate with health
care providers, governments and local communities to support and
expand access to reliable, affordable health care around the world.
For more than 150 years, Pfizer has worked to make a difference for
all who rely on us. To learn more, please visit us at
www.pfizer.com.
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 product development. 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. 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,
2013, 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.
Pfizer Disclosure Notice
The information contained in this release is as of December 8,
2014. Pfizer assumes no obligation to update forward-looking
statements contained in this release as the result of new
information or future events or developments.
This release contains forward-looking information about Eliquis
and 4-factor prothrombin complex concentrates (PCCs), including
their potential benefits, that involves substantial risks and
uncertainties that could cause actual results to differ materially
from those expressed or implied by such statements. Risks and
uncertainties include, among other things, the uncertainties
inherent in research and development, including the possibility of
unfavorable clinical trial results, including unfavorable new
clinical data and additional analyses of existing clinical data;
whether and when any drug applications may be filed for any PCCs
for the reversal of the anticoagulant effect of Eliquis; whether
and when regulatory authorities will approve any such applications;
and competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended
December 31, 2013 and in its subsequent reports on Form 10-Q,
including in the sections thereof captioned “Risk Factors” and
“Forward-Looking Information That May Affect Future Results”, as
well as in its subsequent reports on Form 8-K, all of which are
filed with the SEC and available at www.sec.gov and
www.pfizer.com.
Bristol-Myers SquibbMedia: Danielle Halstrom,
609-419-5512, danielle.halstrom@bms.comInvestors: Ranya
Dajani, 609-252-5330, ranya.dajani@bms.comRyan Asay, 609-252-5020,
ryan.asay@bms.comorPfizer Inc.Media: Steven Danehy,
212-733-1538, steven.danehy@pfizer.comAndrew Widger,
+44-1737-330909, andrew.widger@pfizer.comInvestors: Ryan
Crowe, 212-733-8160, ryan.crowe@pfizer.com
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