U.S. FDA Approves Eliquis (apixaban) for the Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), and for the Reduction in the Risk of Recurrent DVT and PE Following Initial Therapy
* Eliquis demonstrated noninferiority in the primary efficacy endpoint of recurrent symptomatic venous thromboembolism (VTE) or VTE-related death versus enoxaparin/warfarin in the AMPLIFY trial
PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--Bristol-Myers
Squibb Company (NYSE: BMY) and Pfizer
Inc. (NYSE: PFE) today announced the U.S. Food and Drug
Administration (FDA) has approved a Supplemental New Drug Application
(sNDA) for Eliquis for the treatment of DVT and PE, and for the
reduction in the risk of recurrent DVT and PE following initial therapy.
Combined, DVT and PE are known as VTE. It is estimated that every
year, approximately 900,000 Americans are affected by DVT and PE.
“We are pleased that Eliquis is now available as an effective
treatment option for DVT and PE,” said Douglas Manion, M.D.,
Head of Specialty Development, Bristol-Myers Squibb. “Eliquis offers
oral dosing, no routine coagulation testing, and does not
require the use of a parenteral anticoagulant or bridging during
“DVT, which may lead to PE, can be a serious medical condition, with PE
requiring immediate medical attention for treatment. Once a
VTE has occurred, approximately 33 percent of patients are at risk of a
recurrence within 10 years,” said Steve Romano, senior vice president,
Head of Medicines Development Group for Global Innovative
Pharmaceuticals, Pfizer Inc. “The Bristol-Myers Squibb and Pfizer
alliance is committed to delivering important treatment options to
patients and physicians.”
The full Prescribing Information for Eliquis includes Boxed
Warnings for the increased risk of thrombotic events in patients who
prematurely discontinue Eliquis; and for the increased risk of
epidural or spinal hematoma, which may cause long-term or permanent
paralysis, in patients using Eliquis and undergoing spinal
epidural anesthesia or spinal puncture.
Eliquis increases the risk of bleeding and can cause serious,
potentially fatal, bleeding. Please see the complete Boxed Warnings and
additional Important Safety Information in this press release.
The FDA approval of Eliquis for the treatment of DVT and PE, and
for the reduction in the risk of recurrent DVT and PE following initial
therapy, is based on data from the global AMPLIFY and AMPLIFY-EXT
The AMPLIFY study, a randomized, double-blind trial, was designed to
demonstrate the efficacy and safety of Eliquis for the treatment
of DVT and PE, and included patients with confirmed symptomatic DVT or
PE (2,609 for Eliquis and 2,635 for standard of care, which
was initial enoxaparin treatment for at least five days, overlapped by
warfarin therapy [International Normalized Ratio (INR) range 2.0-3.0]
orally for six months).
In the AMPLIFY study, Eliquis 10 mg twice daily for one week
followed by 5 mg twice daily for six months demonstrated efficacy
comparable to standard of care in treating DVT and PE patients for the
primary efficacy composite endpoint of recurrent, symptomatic VTE, or
VTE-related death (2.3% vs. 2.7%, relative risk, 0.84; 95% confidence
interval [CI], 0.60 to 1.18; P-value<0.0001 for noninferiority).
Eliquis demonstrated superiority in the primary safety endpoint
of major bleeding versus standard of care (0.6% vs. 1.8%, relative risk
0.31; 95% CI, 0.17 to 0.55; P<0.0001 for superiority). Major bleeding
was defined as clinically overt bleeding that was accompanied by one or
more of the following: a decrease in the hemoglobin level of 2 g/dL or
more; a transfusion of two or more units of packed red blood cells;
bleeding that occurred in at least one of the following critical sites:
intracranial, intraspinal, intraocular, pericardial, intra-articular,
intramuscular with compartment syndrome, retroperitoneal; or bleeding
that was fatal.
For the secondary safety endpoint in the AMPLIFY study, the event rates
for clinically relevant nonmajor bleeding (CRNM) were fewer in Eliquis-treated
patients compared to standard of care-treated patients (3.9% vs. 8.0%).
CRNM was defined as overt bleeding that did not meet the criteria for
major bleeding but was associated with a medical intervention, contact
with a physician, interruption of the study drug, or discomfort or
impairment in carrying out daily activities.
In AMPLIFY, the discontinuation rate due to bleeding events was 0.7% in
the Eliquis-treated patients compared to 1.7% in
About DVT and PE
DVT is a blood clot in a vein, usually in the lower leg, thigh, or
pelvis, which partially or totally blocks the flow of blood. PE is a
blood clot blocking one or more vessels in the lungs. DVT causes
multiple symptoms including pain, swelling, and redness, and more
importantly, can progress to PE, which carries the risk of sudden death.
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 Important Safety Information
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
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.
Active pathological bleeding
Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic
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,
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
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.
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
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. Among other risks, there can be
no guarantee that the approval of these additional indications in the
U.S. will lead to increased commercial success or that Eliquis will be
approved for any other additional indications. 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 August 21, 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’s
(apixaban’s) potential benefits and about additional indications for
Eliquis in the U.S. for the treatment of DVT and PE, and for the
reduction in the risk of recurrent DVT and PE following initial therapy,
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 regarding the commercial success of the additional
indications in the U.S.; whether and when regulatory authorities in
other jurisdictions will approve applications for these potential
additional indications, as well as their decisions regarding labeling
and other matters that could affect the availability or commercial
potential of such potential additional indications; and competitive
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 our subsequent reports on Form 10-Q, including in the
sections thereof captioned “Risk Factors” and “Forward--10-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