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Drug Discontinuation in RE-LY: The rates of adverse reactions leading to
treatment discontinuation were 21% for PRADAXA 150 mg and 16% for
warfarin. The most frequent adverse reactions leading to discontinuation
of PRADAXA were bleeding and gastrointestinal events (i.e., dyspepsia,
nausea, upper abdominal pain, gastrointestinal hemorrhage, and
diarrhea). Bleeding [see Warnings and Precautions]: Table 2 shows
the number of adjudicated major bleeding events during the treatment
period in the RE-LY study, with the bleeding rate per 100 subject-years
(%). Major bleeding is defined as bleeding accompanied by one or more Table 3 Bleeding Events in RE-COVER and
RE-COVER II Treated Patients
of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion
Bleeding Events-Full Treatment Period
of ≥2 units of packed red blood cells, bleeding at a critical site or
Including Parenteral Treatment
with a fatal outcome. Intracranial hemorrhage included intracerebral
(hemorrhagic stroke), subarachnoid, and subdural bleeds.
PRADAXA
Warfarin
Hazard Ratio
Table 2 Adjudicated Major Bleeding Events in Treated
150 mg twice
N (%)
(95% CI)c
Patientsa
daily N (%)
Event
PRADAXA
PRADAXA
Patients
N=2553
N=2554
Warfarin
150 mg
150 mg
N
=
5998
37 (1.4)
51 (2.0)
0.73
Major bleeding eventa
N = 6059
vs. Warfarin
b
( 0.48, 1.11)
n (%/yearb) n (%/year ) HR (95% CI)
Fatal bleeding
1 (0.04)
2 (0.1)
Major Bleedingc
350 (3.47)
374 (3.58)
0.97
Bleeding in a critical
7 (0.3)
15 (0.6)
(0.84, 1.12)
area or organ
Fall in hemoglobin
32 (1.3)
38 (1.5)
Intracranial Hemor23 (0.22)
82 (0.77)
0.29
≥2g/dL or transfurhage (ICH)d
(0.18, 0.46)
sion ≥2 units of
whole blood or
packed red blood
cells
99
10,659
99.5
10,261
2
21.3
10,242
Total patient-years
1
20.3
0.5
2470
20.5
Mean exposure (months)
98
5193
2405
99
4939
2387
99.5
4936
> 24 months
2
> 12 months
1
5998
0.5
6059
98
5983
Exposure
PRADAXA
150 mg
vs. Warfarin
HR (95% CI)
Hemorrhagic
40 (0.37)
0.16
e
Stroke
(0.07, 0.37)
Other ICH
17 (0.17)
46 (0.43)
0.38
(0.22, 0.67)
Gastrointestinal
162 (1.59)
111 (1.05)
1.51
(1.19, 1.92)
f
Fatal Bleeding
7 (0.07)
16 (0.15)
0.45
(0.19, 1.10)
ICH
3 (0.03)
9 (0.08)
0.35
(0.09, 1.28)
g
Non-intracranial
4 (0.04)
7 (0.07)
0.59
(0.17, 2.02)
a
Patients during treatment or within 2 days of stopping study treatment. Major
bleeding events within each subcategory were counted once per patient, but
patients may have contributed events to multiple subcategories.
b
Annual event rate per 100 pt-years = 100 * number of subjects with event/
subject-years. Subject-years is defined as cumulative number of days from
first drug intake to event date, date of last drug intake + 2, death date
(whatever occurred first) across all treated subjects divided by 365.25. In
case of recurrent events of the same category, the first event was considered.
c
Defined as bleeding accompanied by one or more of the following: a
decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of
packed red blood cells, bleeding at a critical site or with fatal outcome.
d
Intracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid,
and subdural bleeds.
e
On-treatment analysis based on the safety population, compared to ITT
analysis presented in Section 14 Clinical Studies.
f
Fatal bleed: Adjudicated major bleed as defined above with investigator
reported fatal outcome and adjudicated death with primary cause from
bleeding.
g
Non-intracranial fatal bleed: Adjudicated major bleed as defined above and
adjudicated death with primary cause from bleeding but without symptomatic
intracranial bleed based on investigator’s clinical assessment.
There was a higher rate of any gastrointestinal bleeds in patients
receiving PRADAXA 150 mg than in patients receiving warfarin (6.6%
vs. 4.2%, respectively). The risk of major bleeds was similar with
PRADAXA 150 mg and warfarin across major subgroups defined by
baseline characteristics (see Figure 1, below), with the exception of
age, where there was a trend towards a higher incidence of major
bleeding on PRADAXA (hazard ratio 1.2, 95% CI: 1.0 to 1.5) for
patients ≥75 years of age. Gastrointestinal Adverse Reactions:
Patients on PRADAXA 150 mg had an increased incidence of
gastrointestinal adverse reactions (35% vs. 24% on warfarin). These
were commonly dyspepsia (including abdominal pain upper, abdominal
pain, abdominal discomfort, and epigastric discomfort) and gastritislike symptoms (including GERD, esophagitis, erosive gastritis, gastric
hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and
gastrointestinal ulcer). Hypersensitivity Reactions: In the RE-LY study,
drug hypersensitivity (including urticaria, rash, and pruritus), allergic
edema, anaphylactic reaction, and anaphylactic shock were reported in
<0.1% of patients receiving PRADAXA. Treatment and Reduction in
the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary
Embolism: PRADAXA was studied in 4387 patients in 4 pivotal,
parallel, randomized, double-blind trials. Three of these trials were
active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY),
and one study (RE-SONATE) was placebo-controlled. The demographic
characteristics were similar among the 4 pivotal studies and between
the treatment groups within these studies. Approximately 60% of
the treated patients were male, with a mean age of 55.1 years. The
majority of the patients were white (87.7%), 10.3% were Asian, and
1.9% were black with a mean CrCl of 105.6 mL/min. Bleeding events
for the 4 pivotal studies were classified as major bleeding events if at
least one of the following criteria applied: fatal bleeding, symptomatic
bleeding in a critical area or organ (intraocular, intracranial, intraspinal
or intramuscular with compartment syndrome, retroperitoneal bleeding,
intra-articular bleeding, or pericardial bleeding), bleeding causing a fall
in hemoglobin level of 2.0 g/dL (1.24 mmol/L or more, or leading to
transfusion of 2 or more units of whole blood or red cells). RE-COVER
and RE-COVER II studies compared PRADAXA 150 mg twice daily and
warfarin for the treatment of deep vein thrombosis and pulmonary
embolism. Patients received 5-10 days of an approved parenteral
anticoagulant therapy followed by 6 months, with mean exposure of 164
days, of oral only treatment; warfarin was overlapped with parenteral
therapy. Table 3 shows the number of patients experiencing bleeding
events in the pooled analysis of RE-COVER and RE-COVER II studies
during the full treatment including parenteral and oral only treatment
periods after randomization.
Warfarin
N = 5998
n (%/yearb)
99
Total number treated
PRADAXA
150 mg
N = 6059
n (%/yearb)
6 (0.06)
99.5
Table 1 Summary of Treatment Exposure in RE-LY
PRADAXA
PRADAXA
110 mg
150 mg
Warfarin
twice daily twice daily
Table 2 (Cont'd)
Event
25
patients to immediately report if they experience any of the above signs
or symptoms. If signs or symptoms of spinal hematoma are suspected,
initiate urgent diagnosis and treatment including consideration for spinal
cord decompression even though such treatment may not prevent or
reverse neurological sequelae. Thromboembolic and Bleeding
Events in Patients with Prosthetic Heart Valves: The safety and
efficacy of PRADAXA in patients with bileaflet mechanical prosthetic
heart valves was evaluated in the RE-ALIGN trial, in which patients
with bileaflet mechanical prosthetic heart valves (recently implanted or
implanted more than three months prior to enrollment) were randomized
to dose adjusted warfarin or 150, 220, or 300 mg of PRADAXA twice a
day. RE-ALIGN was terminated early due to the occurrence of significantly
more thromboembolic events (valve thrombosis, stroke, transient
ischemic attack, and myocardial infarction) and an excess of major
bleeding (predominantly post-operative pericardial effusions requiring
intervention for hemodynamic compromise) in the PRADAXA treatment
arm as compared to the warfarin treatment arm. These bleeding and
thromboembolic events were seen both in patients who were initiated on
PRADAXA post-operatively within three days of mechanical bileaflet valve
implantation, as well as in patients whose valves had been implanted
more than three months prior to enrollment. Therefore, the use of
PRADAXA is contraindicated in patients with mechanical prosthetic
valves [see Contraindications]. The use of PRADAXA for the prophylaxis
of thromboembolic events in pat ients with atrial fibrillation in the setting
of other forms of valvular heart disease, including the presence of a
bioprosthetic heart valve, has not been studied and is not recommended.
Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure:
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin)
reduces exposure to dabigatran and should generally be avoided. P-gp
inhibition and impaired renal function are the major independent factors
that result in increased exposure to dabigatran. Concomitant use of
P-gp inhibitors in patients with renal impairment is expected to produce
increased exposure of dabigatran compared to that seen with either factor
alone. Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: Reduce the dose of PRADAXA to 75 mg twice
daily when dronedarone or systemic ketoconazole is coadministered with
PRADAXA in patients with moderate renal impairment (CrCl 30-50 mL/
min). Avoid use of PRADAXA and P-gp inhibitors in patients with severe
renal impairment (CrCl 15-30 mL/min) [see Drug Interactions and
Use in Specific Populations]. Treatment and Reduction in the Risk of
Recurrence of Deep Venous Thrombosis and Pulmonary Embolism:
Avoid use of PRADAXA and concomitant P-gp inhibitors in patients with
CrCl <50 mL/min [see Drug Interactions].
ADVERSE REACTIONS: The following serious adverse reactions are
described elsewhere in the labeling: Increased Risk of Thrombotic Events
after Premature Discontinuation [see Warnings and Precautions]; Risk
of Bleeding [see Warnings and Precautions]; Spinal/Epidural Anesthesia
or Puncture [see Warnings and Precautions]; Thromboembolic and
Bleeding Events in Patients with Prosthetic Heart Valves [see Warnings
and Precautions]. The most serious adverse reactions reported with
PRADAXA were related to bleeding [see Warnings and Precautions].
Clinical Trials Experience: Because clinical trials are conducted under
widely varying conditions, adverse reactions rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
Reduction of Risk of Stroke and Systemic Embolism in Non-valvular
Atrial Fibrillation: The RE-LY (Randomized Evaluation of Long-term
Anticoagulant Therapy) study provided safety information on the use of
two doses of PRADAXA and warfarin. The numbers of patients and their
exposures are described in Table 1. Limited information is presented on
the 110 mg dosing arm because this dose is not approved.
Large Trim: 14.25”
Small Trim: 14”
Live: 13”
INDICATIONS AND USAGE: Reduction of Risk of Stroke and
Systemic Embolism in Non-valvular Atrial Fibrillation: PRADAXA
is indicated to reduce the risk of stroke and systemic embolism in
patients with non-valvular atrial fibrillation. Treatment of Deep Venous
Thrombosis and Pulmonary Embolism: PRADAXA is indicated for
the treatment of deep venous thrombosis and pulmonary embolism
in patients who have been treated with a parenteral anticoagulant for
5-10 days. Reduction in the Risk of Recurrence of Deep Venous
Thrombosis and Pulmonary Embolism: PRADAXA is indicated to
reduce the risk of recurrence of deep venous thrombosis and pulmonary
embolism in patients who have been previously treated.
CONTRAINDICATIONS: PRADAXA is contraindicated in patients with:
Active pathological bleeding [see Warnings and Precautions and
Adverse Reactions]; History of a serious hypersensitivity reaction to
PRADAXA (e.g., anaphylactic reaction or anaphylactic shock) [see
Adverse Reactions]; Mechanical prosthetic heart valve [see Warnings
and Precautions].
WARNINGS AND PRECAUTIONS: Increased Risk of Thrombotic
Events after Premature Discontinuation: Premature discontinuation
of any oral anticoagulant, including PRADAXA, in the absence of adequate
alternative anticoagulation increases the risk of thrombotic events. If
PRADAXA is discontinued for a reason other than pathological bleeding
or completion of a course of therapy, consider coverage with another
anticoagulant and restart PRADAXA as soon as medically appropriate.
Risk of Bleeding: PRADAXA increases the risk of bleeding and can
cause significant and, sometimes, fatal bleeding. Promptly evaluate
any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or
hematocrit or hypotension). Discontinue PRADAXA in patients with active
pathological bleeding. Risk factors for bleeding include the concomitant
use of other drugs that increase the risk of bleeding (e.g., anti-platelet
agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs).
PRADAXA’s anticoagulant activity and half-life are increased in patients
with renal impairment. Reversal of Anticoagulant Effect: A specific
reversal agent (idarucizumab) for dabigatran is available when reversal
of the anticoagulant effect of dabigatran is needed: For emergency
surgery/urgent procedures; In life-threatening or uncontrolled bleeding.
Hemodialysis can remove dabigatran; however the clinical experience
supporting the use of hemodialysis as a treatment for bleeding is limited
[see Overdosage]. Prothrombin complex concentrates, or recombinant
Factor VIIa may be considered but their use has not been evaluated
in clinical trials. Protamine sulfate and vitamin K are not expected to
affect the anticoagulant activity of dabigatran. Consider administration
of platelet concentrates in cases where thrombocytopenia is present
or long-acting antiplatelet drugs have been used. Spinal/Epidural
Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural
anesthesia) or spinal puncture is employed, patients treated with
anticoagulant agents are at risk of developing an epidural or spinal
hematoma which can result in long-term or permanent paralysis [see
Boxed Warning]. To reduce the potential risk of bleeding associated
with the concurrent use of dabigatran and epidural or spinal anesthesia/
analgesia or spinal puncture, consider the pharmacokinetic profile
of dabigatran. Placement or removal of an epidural catheter or
lumbar puncture is best performed when the anticoagulant effect of
dabi gatran is low; however, the exact timing to reach a sufficiently low
anticoagulant effect in each patient is not known. Should the physician
decide to administer anticoagulation in the context of epidural or
spinal anesthesia/analgesia or lumbar puncture, monitor frequently
to detect any signs or symptoms of neurological impairment, such as
midline back pain, sensory and motor deficits (numbness, tingling, or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct
CARDIOSOURCE WORLD NEWS
50
WARNING: (A) PREMATURE DISCONTINUATION
OF PRADAXA INCREASES THE RISK OF
THROMBOTIC EVENTS,
(B) SPINAL/EPIDURAL HEMATOMA
(A) PREMATURE DISCONTINUATION OF PRADAXA
INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant,
including PRADAXA, increases the risk of thrombotic
events. If anticoagulation with PRADAXA is discontinued
for a reason other than pathological bleeding or completion
of a course of therapy, consider coverage with another
anticoagulant [see Warnings and Precautions].
(B) SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients treated
with PRADAXA 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 non-steroidal antiinflammatory 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 PRADAXA
and neuraxial procedures is not known [see Warnings
and Precautions].
Monitor patients frequently for signs and symptoms of
neurological impairment. If neurological compromise is
noted, urgent treatment is necessary [see Warnings and
Precautions].
Consider the benefits and risks before neuraxial
intervention in patients anticoagulated or to be
anticoagulated [see Warnings and Precautions].
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Pradaxa® (dabigatran etexilate mesylate)
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BRIEF SUMMARY OF PRESCRIBING INFORMATION
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