Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Bleeding
(Additions and/or
revisions underlined)
ELIQUIS
increases the risk of bleeding and can cause serious, potentially fatal, bleeding.
Concomitant
use of drugs affecting hemostasis increases the risk of bleeding. These include
aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic
agents, selective serotonin reuptake inhibitors, serotonin norepinephrine
reuptake inhibitors, and nonsteroidal anti- inflammatory drugs (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.
Reversal of Anticoagulant Effect
An
agent to reverse the anti-factor Xa activity of apixaban is available. The pharmacodynamic
effect of ELIQUIS can be expected to persist for at least 24 hours after the last
dose, i.e., for about two drug half-lives. Prothrombin complex concentrate (PCC),
activated prothrombin complex concentrate or recombinant factor VIIa may be considered,
but have not been evaluated in clinical studies. When PCCs are used, monitoring
for the anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT)
or anti-factor Xa (FXa) activity is not useful and is not recommended. Activated
oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration.
Hemodialysis
does not appear to have a substantial impact on apixaban exposure. Protamine sulfate
and vitamin K are not 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 no experience with systemic hemostatics
(desmopressin) in individuals receiving ELIQUIS, and they are not expected
to be effective as a reversal agent.
5.6 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome
(Newly added
subsection)
Direct-acting
oral anticoagulants (DOACs), including ELIQUIS, are not recommended for use in patients
with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially
those who are triple positive [positive for lupus anticoagulant, anticardiolipin,
and anti–beta 2- glycoprotein I antibodies]), treatment with DOACs has been associated
with increased rates of recurrent thrombotic events compared with vitamin K
antagonist therapy.
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or
revisions underlined)
…
In
ARISTOTLE, the results for major bleeding were generally consistent across most
major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to
estimate risk of stroke, with higher scores predicting greater risk), prior warfarin
use, geographic region, and aspirin use at randomization (Figure 1). Subjects
treated with ELIQUIS with diabetes bled more (3% per year) than did
subjects without diabetes (1.9% per year).
…
Less
common adverse reactions in ELIQUIS-treated patients undergoing hip or
knee replacement surgery occurring at a frequency of greater than or equal to 0.1%
to <1%:
Blood and lymphatic
system disorders: thrombocytopenia
(including platelet count decreases)
Vascular disorders:
hypotension
(including procedural hypotension)
Respiratory, thoracic,
and mediastinal disorders: epistaxis
Gastrointestinal disorders:
gastrointestinal
hemorrhage (including hematemesis and melena), hematochezia
Hepatobiliary disorders:
liver
function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased
Renal and urinary
disorders: hematuria
(including respective laboratory parameters)
Injury, poisoning,
and procedural complications: wound secretion, incision-site hemorrhage (including
incision-site hematoma), operative hemorrhage
Less
common adverse reactions in ELIQUIS-treated patients undergoing hip or
knee replacement surgery occurring at a frequency of <0.1%:
…
7
Drug Interactions
7.3 Anticoagulants and Antiplatelet Agents
(Additions and/or
revisions underlined)
Coadministration
of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases
the risk of bleeding.
APPRAISE-2,
a placebo-controlled clinical trial of ELIQUIS 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 ELIQUIS compared
to placebo. The rate of ISTH major bleeding was 2.8% per year with ELIQUIS
versus 0.6% per year with placebo in patients receiving single antiplatelet therapy
and was 5.9% per year with ELIQUIS versus 2.5% per year with placebo in
those receiving dual antiplatelet therapy.
In
ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS from
1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin increased
the bleeding risk from 2.7% per year to 4.6% per year. In this clinical trial, there
was limited (2.3%) use of dual antiplatelet therapy with ELIQUIS.
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or
revisions underlined)
Risk
Summary
The
limited available data on ELIQUIS use in pregnant women are insufficient to inform
drug- associated risks of major birth defects, miscarriage, or adverse developmental
outcomes. Treatment may increase the risk of bleeding during pregnancy and delivery.
In animal reproduction studies, no adverse developmental effects were seen when
apixaban was administered to rats (orally), rabbits (intravenously) and mice (orally)
during organogenesis at unbound apixaban exposure levels up to 4, 1 and 19 times,
respectively, the human exposure based on area under plasma-concentration time curve
(AUC) at the Maximum Recommended Human Dose (MRHD) of 5 mg twice daily.
The
estimated background risk of major birth defects and miscarriage for the indicated
populations is unknown. All pregnancies have a background risk of birth defect,
loss, or other adverse outcomes. In the U.S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized pregnancies
is 2% to 4% and 15% to 20%, respectively.
Clinical
Considerations
Disease-associated
maternal and/or embryo/fetal risk
Pregnancy
confers an increased risk of thromboembolism that is higher for women with underlying
thromboembolic disease and certain high-risk pregnancy conditions. Published data
describe that women with a previous history of venous thrombosis are at high risk
for recurrence during pregnancy.
Fetal/Neonatal adverse
reactions
Use
of anticoagulants, including ELIQUIS, may increase the risk of bleeding in
the fetus and neonate.
Labor or delivery
All
patients receiving anticoagulants, including pregnant women, are at risk for bleeding.
ELIQUIS use during labor or delivery in women who are receiving neuraxial anesthesia
may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant
as delivery approaches.
Data
Animal Data
No
developmental toxicities were observed when apixaban was administered during organogenesis
to rats (orally), rabbits (intravenously) and mice (orally) at unbound apixaban
exposure levels 4, 1, and 19 times, respectively, the human exposures at the MRHD.
There was no evidence of fetal bleeding, although conceptus exposure was confirmed
in rats and rabbits. Oral administration of apixaban to rat dams from gestation
day 6 through lactation day 21 at maternal unbound apixaban exposures ranging from
1.4 to 5 times the human exposures at the MRHD was not associated with reduced maternal
mortality or reduced conceptus/neonatal viability, although increased incidences
of peri-vaginal bleeding were observed in dams at all doses. There was no evidence
of neonatal bleeding.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions and/or
revisions underlined)
…
Call your doctor or
get medical help right away if you have any of these signs or symptoms of bleeding
when taking ELIQUIS:
unexpected
bleeding, or bleeding that lasts a long time, such as:
unusual
bleeding from the gums
nosebleeds
that happen often
menstrual
bleeding or vaginal bleeding that is heavier than normal
bleeding
that is severe or you cannot control
red,
pink, or brown urine
red
or black stools (looks like tar)
cough
up blood or blood clots
vomit
blood or your vomit looks like coffee grounds
unexpected
pain, swelling, or joint pain
headaches,
feeling dizzy or weak
ELIQUIS is not for
patients with artificial heart valves.
Spinal or epidural
blood clots (hematoma). People who take a blood thinner medicine
(anticoagulant) like ELIQUIS, and have medicine injected into their spinal and epidural
area, or have a spinal puncture have a risk of forming a blood clot that can cause
long-term or permanent loss of the ability to move (paralysis). Your risk of developing
a spinal or epidural blood clot is higher if:
a
thin tube called an epidural catheter is placed in your back to give you certain
medicine
you
take NSAIDs or a medicine to prevent blood from clotting
you
have a history of difficult or repeated epidural or spinal punctures
- you
have a history of problems with your spine or have had surgery on your spine
If
you take ELIQUIS and receive spinal anesthesia or have a spinal puncture, your doctor
should watch you closely for symptoms of spinal or epidural blood clots or bleeding.
Tell your doctor right away if you have tingling, numbness, or muscle weakness,
especially in your legs and feet.
- ELIQUIS is not for use in people with antiphospholipid
syndrome (APS), especially with positive triple antibody testing, who have a history
of blood clots.
…
What should I tell
my doctor before taking ELIQUIS? Before you take ELIQUIS, tell your doctor if you:
have
kidney or liver problems
have antiphospholipid syndrome
have
any other medical condition
have
ever had bleeding problems
are
pregnant or plan to become pregnant. It is not known if ELIQUIS will harm your unborn
baby.
- are
breastfeeding or plan to breastfeed. It is not known if ELIQUIS passes into your
breast milk. You and your doctor should decide if you will take ELIQUIS or breastfeed.
You should not do both.
Tell
all of your doctors and dentists that you are taking ELIQUIS. They should talk to
the doctor who prescribed ELIQUIS for you, before you have any surgery, medical or dental procedure.
…
Approved Drug Label (PDF)
7
Drug Interactions
Additions
and/or revisions underlined:
7.1 Combined P-gp and Strong CYP3A4
Inhibitors
For patients
receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should be
decreased by 50% when coadministered with drugs that are combined P-gp and
strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir).
For patients
receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with combined
P-gp and strong CYP3A4 inhibitors.
Clarithromycin
Although
clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic
data suggest that no dose adjustment is necessary with concomitant
administration with ELIQUIS.
7.2 Combined
P-gp and Strong CYP3A4 Inducers
Avoid concomitant use of ELIQUIS with combined
P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine,
phenytoin, St. John’s wort) because such drugs will decrease exposure to
apixaban.
8
Use in Specific Populations
8.5 Geriatric Use
Throughout
this entire subsection, years of age is
added following every numerical age.
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