In the AMPLIFY trial, Eliquis was shown to
be non-inferior for the treatment of recurrent venous
thromboembolism (VTE)/VTE-related death and was statistically
superior in the primary safety endpoint of major bleeding vs.
enoxaparin/warfarin
In the AMPLIFY-EXT trial, Eliquis
demonstrated a superior reduction in VTE/all-cause death with no
statistical difference in major bleeding events vs. placebo
Bristol-Myers Squibb Company (NYSE:BMY) and Pfizer Inc.
(NYSE:PFE) today announced that the European Commission has
approved Eliquis for the treatment of DVT and PE, and the
prevention of recurrent DVT and PE in adults. The European
Commission approval applies to all European Union (EU) member
states as well as Iceland and Norway. Eliquis is also approved in
the EU for the prevention of venous thromboembolism (VTE) in adults
who have undergone elective total hip or knee replacement surgery,
and for the prevention of stroke and systemic embolism in adult
patients with nonvalvular atrial fibrillation (NVAF) with one or
more risk factors.
“Every year, approximately one million patients in the EU are
diagnosed with VTE,” said Dr. Elliott Levy, senior vice president,
head of Specialty Development, Bristol-Myers Squibb. “Once a VTE
has occurred, approximately 33 percent of patients may experience a
recurrence within 10 years.”
The marketing authorization for Eliquis follows the positive
opinion issued by the Committee for Medicinal Products for Human
Use (CHMP) of the European Medicines Agency, and is supported by
two pivotal Phase 3 clinical trials, AMPLIFY and AMPLIFY-EXT.
AMPLIFY (Apixaban for the initial Management of
PuLmonary embolIsm and deep vein thrombosis as
First-line therapY) was designed to demonstrate the
efficacy and safety of Eliquis for the treatment of DVT and PE
versus enoxaparin 1 mg/kg twice daily subcutaneously for at least 5
days (until INR≥ 2) and warfarin (target INR range 2.0-3.0) orally
for six months. AMPLIFY-EXT (Apixaban after the initial
Management of PuLmonary embolIsm and
deep vein thrombosis with First-line therapY-EXTended
treatment) was designed to demonstrate the efficacy and safety of
Eliquis compared to placebo for the prevention of recurrent DVT and
PE following six to 12 months of anticoagulant treatment for DVT
and/or PE.
“The European Commission’s approval of Eliquis for the treatment
of DVT and PE and the prevention of recurrence is an important
milestone and demonstrates Bristol-Myers Squibb and Pfizer’s
ongoing commitment to bringing innovative medicines to patients who
need them,” said Steve Romano, senior vice president, head of
Medicines Development Group for Global Innovative Pharmaceuticals,
Pfizer Inc.
About the Clinical Trial Program
AMPLIFY
As described in the SmPC, in the AMPLIFY study a total of 5,395
patients were randomized to treatment with Eliquis 10 mg twice
daily orally for seven days followed by Eliquis 5 mg twice daily
orally for six months, or enoxaparin 1 mg/kg twice daily
subcutaneously for at least five days (until INR≥ 2) and warfarin
(target INR range 2.0-3.0) orally for six months.
The mean age was 56.9 years and 89.8 percent of randomized
patients had unprovoked VTE events.
In the study, Eliquis was shown to be non-inferior to
enoxaparin/warfarin in the combined primary endpoint of adjudicated
recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or
VTE-related death.
Eliquis efficacy in initial treatment of VTE was consistent
between patients who were treated for a PE [Relative Risk 0.9; 95
percent CI (0.5, 1.6)] or DVT [Relative Risk 0.8; 95 percent CI
(0.5, 1.3)]. Efficacy across subgroups, including age, gender, body
mass index (BMI), renal function, extent of index PE, location of
DVT thrombus, and prior parenteral heparin use was generally
consistent.
For patients randomized to warfarin, the mean percentage of time
in therapeutic range (TTR) (INR 2.0-3.0) was 60.9. The effect of
Eliquis on recurrent symptomatic VTE or VTE- related death was
consistent across the different levels of center TTR; within the
highest quartile of TTR according to center, the relative risk for
Eliquis vs enoxaparin/warfarin was 0.79 (95 percent CI, 0.39,
1.61).
The primary safety endpoint was major bleeding. In the study,
Eliquis was statistically superior to enoxaparin/warfarin in the
primary safety endpoint [Relative Risk 0.31, 95 percent confidence
interval (0.17, 0.55), P-value <0.0001].
The adjudicated major bleeding and clinically relevant non-major
(CRNM) bleeding at any anatomical site were generally lower in the
Eliquis group as compared to the enoxaparin/warfarin group.
Adjudicated International Society on Thrombosis and Haemostasis
(ISTH) major gastrointestinal bleeding occurred in 6 (0.2 percent)
Eliquis-treated patients and 17 (0.6 percent)
enoxaparin/warfarin-treated patients.
AMPLIFY- EXT
As described in the SmPC, in the AMPLIFY-EXT study a total of
2,482 patients were randomized to treatment with Eliquis 2.5 mg
twice daily orally, Eliquis 5 mg twice daily orally, or placebo for
12 months after completing six to 12 months of initial
anticoagulant treatment. Of these, 836 patients (33.7 percent)
participated in the AMPLIFY study prior to enrollment in the
AMPLIFY-EXT study.
The mean age was 56.7 years and 91.7 percent of randomized
patients had unprovoked VTE events.
In the study, both doses of Eliquis were statistically superior
to placebo in the primary endpoint of symptomatic, recurrent VTE
(nonfatal DVT or nonfatal PE) or all-cause death.
Eliquis efficacy for prevention of a recurrence of a VTE was
maintained across subgroups, including age, gender, BMI, and renal
function.
The primary safety endpoint was major bleeding during the
treatment period. In the study, the incidence in major bleeding for
both Eliquis doses was not statistically different from placebo.
There was no statistically significant difference in the incidence
of major, clinically relevant non-major, minor, and all bleeding
between the Eliquis 2.5 mg twice daily and placebo treatment
groups. The recommended dose of Eliquis for the prevention of
recurrent DVT and PE is 2.5 mg taken orally twice daily.
Adjudicated ISTH major gastrointestinal bleeding occurred in 1
(0.1 percent) Eliquis-treated patient at the 5 mg twice daily dose,
no patients at the 2.5 mg twice daily dose, and 1 (0.1 percent)
placebo-treated patient.
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 to reduce the risk of stroke and systemic embolism in
adult patients with NVAF in the United States, European Union,
Japan and a number of other countries around the world. Eliquis is
approved for the prophylaxis of VTE in adult patients who have
undergone elective hip or knee replacement surgery in the United
States, European Union and a number of other countries around the
world. Eliquis is not approved for this indication in Japan.
Eliquis is approved for the treatment of DVT and PE, and prevention
of recurrent DVT and PE in the European Union. Eliquis is not
approved for this indication in the United States.
IMPORTANT SAFETY INFORMATION FROM U.S.
PRESCRIBING INFORMATION
WARNINGS: (A) DISCONTINUING ELIQUIS IN PATIENTS WITH
NONVALVULAR ATRIAL FIBRILLATION WITHOUT ADEQUATE CONTINUOUS
ANTICOAGULATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL
HEMATOMA
(A) Discontinuing ELIQUIS places patients at an increased
risk of thrombotic events. An increased rate of stroke was observed
following discontinuation of ELIQUIS in clinical trials in patients
with nonvalvular atrial fibrillation. If anticoagulation with
ELIQUIS must be discontinued for a reason other than pathological
bleeding, coverage with another anticoagulant should be strongly
considered.
(B) When neuraxial anesthesia (epidural/spinal anesthesia) or
spinal puncture is employed, patients anticoagulated or scheduled
to be anticoagulated with low molecular weight heparins,
heparinoids, or Factor Xa inhibitors for prevention of
thromboembolic complications are at risk of developing an epidural
or spinal hematoma which can result in long-term or permanent
paralysis.
The risk of these events may be increased by the use of
indwelling epidural catheters for administration of analgesia or by
the concomitant use of drugs affecting hemostasis such as
nonsteroidal anti-inflammatory drugs (NSAIDs), platelet aggregation
inhibitors, or other anticoagulants. The risk also appears to be
increased by traumatic or repeated epidural or spinal
puncture.
Monitor patients for signs and symptoms of neurologic
impairment. If neurologic compromise is noted, urgent treatment is
necessary. Consider the potential benefit versus risk before
neuraxial intervention in patients anticoagulated or to be
anticoagulated for thromboprophylaxis
CONTRAINDICATIONS
- Active pathological bleeding
- Severe hypersensitivity reaction to
ELIQUIS (apixaban) (e.g., anaphylactic reactions)
WARNINGS AND PRECAUTIONS
- Increased Risk of Stroke with
Discontinuation of ELIQUIS in Patients with Nonvalvular Atrial
Fibrillation: Discontinuing 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 patients
with nonvalvular atrial fibrillation. If ELIQUIS must be
discontinued for a reason other than pathological bleeding,
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. Patients should be made aware of signs or
symptoms of blood loss and instructed to immediately report 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.
Hemodialysis does not appear to have a substantial impact on
apixaban exposure. Protamine sulfate and vitamin K would not be
expected to affect the anticoagulant activity of apixaban. There is
no experience with antifibrinolytic agents (tranexamic acid,
aminocaproic acid) in individuals receiving apixaban. There is
neither scientific rationale for reversal nor experience with
systemic hemostatics (desmopressin and aprotinin) in individuals
receiving apixaban. Use of procoagulant reversal agents such as
prothrombin complex concentrate, activated prothrombin complex
concentrate, or recombinant factor VIIa may be considered but has
not been evaluated in clinical studies. Activated charcoal reduces
absorption of apixaban thereby lowering apixaban plasma
concentrations.
- 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.
ADVERSE REACTIONS
The most common and most serious adverse reactions reported with
ELIQUIS (apixaban) 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
5 mg twice daily, the dose of ELIQUIS should be decreased when it
is coadministered with drugs that are strong dual inhibitors of
CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or
clarithromycin). In patients already taking 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.
- 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 DVT and PE
Venous thromboembolism, or VTE, encompasses two serious
conditions: deep vein thrombosis (DVT) and pulmonary embolism (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. Approximately one million patients in the EU are diagnosed
every year with VTE.
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.
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 Europe will lead to increased commercial
success or that Eliquis will be approved for these additional
indications in the U.S. or in other countries. 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 July 29,
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 EU for the treatment of deep vein
thrombosis (DVT) and pulmonary embolism (PE) and the prevention of
recurrent DVT and PE in adults 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 EU; whether and when the FDA or 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 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 our 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 Squibb CompanyMedia:Shelly Mittendorf,
609-252-5799shelly.mittendorf@bms.comorInvestors:Ranya
Dajani, 609-252-5330ranya.dajani@bms.comorRyan Asay,
609-252-5020ryan.asay@bms.comorPfizer Inc.Media:Jennifer
Kokell,
212-733-2596jennifer.kokell@pfizer.comorInvestors:Ryan
Crowe, 212-733-8160ryan.crowe@pfizer.com
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