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 [see Dosage and Administration (2.4, 2.5, 2.6) ].
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
[see Dosage and Administration ]
.
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
[see Clinical Pharmacology ]
.
Reversal of Anticoagulant Effect:
A specific reversal agent for dabigatran is not available.
Hemodialysis can remove dabigatran; however the clinical experience
supporting the use of hemodialysis as a treatment for bleeding is
limited [see Overdosage ]. Activated prothrombin complex concentrates (aPCCs, e.g.,
FEIBA), or recombinant Factor VIIa, or concentrates of coagulation
factors II, IX or X 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 [see Clinical Pharmacology ]. Placement or removal of an epidural catheter or lumbar
puncture is best performed when the anticoagulant effect of dabigatran
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
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 ProstheticHeart 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 (4) ].
The use
of PRADAXA for the prophylaxis of thromboembolic events in patients
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 [see Clinical Pharmacology ].
P-gp inhibition and impaired renal function are the
major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology ]. 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 Non-valvular Atrial Fibrillation
Consider reducing 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 and Use in Specific Populations ].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in
pregnant women.
Dabigatran has
been shown to decrease the number of implantations when male and female
rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times
the human exposure at maximum recommended human dose [MRHD] of 300
mg/day based on area under the curve [AUC] comparisons) prior to mating
and up to implantation (gestation Day 6). Treatment of pregnant rats
after implantation with dabigatran at the same dose increased the
number of dead offspring and caused excess vaginal/uterine bleeding
close to parturition. Although dabigatran increased the incidence
of delayed or irregular ossification of fetal skull bones and vertebrae
in the rat, it did not induce major malformations in rats or rabbits.
Labor and Delivery
Safety and effectiveness of PRADAXA during labor and delivery have
not been studied in clinical trials. Consider the risks of bleeding
and of stroke in using PRADAXA in this setting [see Warnings
and Precautions ].
Death of offspring and mother rats during
labor in association with uterine bleeding occurred during treatment
of pregnant rats from implantation (gestation Day 7) to weaning (lactation
Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the
human exposure at MRHD of 300 mg/day based on AUC comparisons).
Nursing Mothers
It is not known whether dabigatran is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential
for serious adverse reactions in nursing infants from PRADAXA, a decision
should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety
and effectiveness of PRADAXA in pediatric patients have not been established.
Geriatric Use
Of
the total number of patients in the RE-LY study, 82% were 65 and over,
while 40% were 75 and over. The risk of stroke and bleeding increases
with age, but the risk-benefit profile is favorable in all age groups [see Warnings and Precautions (5),
Adverse Reactions , and Clinical
Studies ].
Renal Impairment
Reduction of Risk of Stroke and Systemic Embolism in Non-valvular
Atrial Fibrillation
No dose adjustment of PRADAXA is recommended in patients
with mild or moderate renal impairment [see Clinical Pharmacology ]. Reduce the dose of PRADAXA
in patients with severe renal impairment (CrCl 15-30 mL/min) [see Dosage and Administration (2.1, 2.2) and Clinical Pharmacology ]. Dosing recommendations
for patients with CrCl <15 mL/min or on dialysis cannot be provided.
Adjust dose appropriately in patients with
renal impairment receiving concomitant P-gp inhibitors [see
Warnings and Precautions , Drug
Interactions , and Clinical
Pharmacology ].
Treatment and Reduction in the Risk of Recurrence of Deep
Venous Thrombosis and Pulmonary Embolism
Patients with severe renal impairment
(CrCL <30 mL/min) were excluded from RE-COVER.
Dosing recommendations for patients with
CrCl <30 mL/min or on dialysis cannot be provided. Avoid use of
PRADAXA with concomitant P-gp inhibitors in patients with CrCl <50
mL/min [see Warnings and Precautions , Drug Interactions , and Clinical Pharmacology ].
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