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Important Safety Information

STARTING ADULT PATIENTS ON PRADAXA CAPSULES

Assess renal function prior to initiating treatment with PRADAXA Capsules1

Indication-specific dosage strengths available: 75 mg, 110 mg, and 150 mg Capsules

Dosing Information

White icon of a glass of water on a blue background
Should be taken with a full glass of water1
Blue square sign with white symbols of a fork, plate, and knife
Taken with or without food1
Blue square sign with white icon of a INR monitoring
No INR monitoring required1
Rapid Onset of PRADAXA: Maximum Plasma Concentrations Achieved in 1-3 Hours
Rapid onset-maximum plasma concentrations achieved 1-3 hours after administration1
PRADAXA Not Metabolized by Cytochrome P450 System
Not metabolized by the cytochrome P450 system1

Periodically assess renal function as clinically indicated and adjust therapy accordingly1

  • Assess more frequently in clinical situations that may be associated with a decline in renal function

  • Discontinue PRADAXA in adult patients who develop acute renal failure and consider alternative anticoagulant therapy

  • Generally, the extent of anticoagulation does not need to be assessed. When necessary, use aPTT and not INR to assess for anticoagulant activity in adult patients on PRADAXA

When converting adult patients to PRADAXA Capsules from:

  • Warfarin: Discontinue warfarin and start PRADAXA when INR is <2.01

  • Parenteral anticoagulants: Start PRADAXA 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (eg, intravenous unfractionated heparin)1

PRADAXA CAPSULES: DOSING FOR MULTIPLE USES IN ADULT PATIENTS1

Recommended Dosing

Reduce Stroke Risk in NVAF150 mg Twice DailyPatients with CrCl >30 mL/min
75 mg Twice DailyPatients with CrCl 15-30 mL/min
Treat DVT & PE or Reduce Risk of Recurrence

150 mg Twice Daily

For treatment only: Initial treatment with parenteral anticoagulant for 5-10 days

Patients with CrCl >30 mL/min
Reduce DVT & PE Risk After Hip Replacement Surgery

110 mg

1-4 hours post-surgery and after achieving hemostasis, then

220 mg Once Daily

for 28-35 days

Patients with CrCl >30 mL/min

Dosing recommendation cannot be provided for adult patients with

  • NVAF: CrCl <15 mL/min or on dialysis

  • DVT/PE & HIP: CrCl ≤30 mL/min or on dialysis

Dosing With Concomitant Use of P-gp Inhibitors

Reduce Stroke Risk in NVAF150 mg Twice Daily

Patients with CrCl >50 mL/min

75 mg Twice Daily

Patients with CrCl 30-50 mL/min with dronedarone or systemic ketoconazole

Treat DVT & PE or Reduce Risk of Recurrence

150 mg Twice Daily

For treatment only: Initial treatment with parenteral anticoagulant for 5-10 days

Patients with CrCl ≥50 mL/min

Reduce DVT & PE Risk After Hip Replacement Surgery

110 mg

1-4 hours post-surgery and after achieving hemostasis, then

220 mg Once Daily

for 28-35 days

Patients with CrCl ≥50 mL/min

Avoid co-administration in adult patients with

  • NVAF: CrCl <30 mL/min

  • DVT/PE & HIP: CrCl <50 mL/min

CONVERTING ADULT PATIENTS ON PRADAXA TO AND FROM OTHER ANTICOAGULANTS

Discontinue warfarin & Start PRADAXA when the INR is <2.0 

Adjust the starting time of warfarin based on CrCI as follows:

Recommended start of warfarin before discontinuing PRADAXACreatinine clearance
3 days≥50 mL/min
2 days30-50 mL/min
1 day15-30 mL/min
No recommendations can be made<15 mL/min

Because PRADAXA can increase INR, the INR will better reflect warfarin’s effect only after PRADAXA has been stopped for at least 2 days.

Administration of parental anticoagulantRecommended starting time of PRADAXA
Scheduled dosing0 to 2 hours before time of next dose
Continuous infusion
(e.g., intravenous unfractionated heparin)		At the time of discontinuation

Before initiating treatment with a parenteral anticoagulant:

Wait 12 hours after last dose of PRADAXA

CrCl ≥30 mL/min

Wait 24 hours after last dose of PRADAXA

CrCl <30 mL/min

DISCONTINUING PRADAXA FOR SURGERY AND OTHER INTERVENTIONS1

Half-life

  • Healthy subjects: 12-17 hours

Before invasive or surgical procedures

  • Due to an increased risk of bleeding, PRADAXA should be discontinued before invasive or surgical procedures, if possible:

Discontinue 1-2 days before procedure

CrCl ≥50 mL/min

Discontinue 3-5 days before procedure

CrCl <50 mL/min

Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal epidural catheter or port, in whom complete hemostasis may be required

Additional Guidance

Risk of bleeding1

If surgery cannot be delayed, there is an increased risk of bleeding

  • This risk of bleeding should be weighed against the urgency of intervention

Use the specific reversal agent Praxbind® (idarucizumab) in case of emergency surgery or urgent procedures when reversal of the anticoagulant effect of dabigatran is needed

  • Refer to the prescribing information for PRAXBIND for additional information

  • Restart PRADAXA as soon as medically appropriate

Discontinuation and increased risk of thrombotic events1

  • 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, consider coverage with another anticoagulant and restart PRADAXA as soon as medically appropriate

ASSESSING ANTICOAGULATION ACTIVITY OF PRADAXA

General guidelines for assessment

INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring1

When assessment is necessary, use aPTT and not INR to assess for anticoagulant activity in adult patients on PRADAXA1

  • PRADAXA prolongs aPTT at therapeutic doses1

When possible, determine time of last dose of PRADAXA relative to time of blood sampling2

Anticoagulant effect

aPTT provides an approximation of anticoagulant effect1

  • Prolongation of aPTT occurs with increasing PRADAXA plasma concentration2

  • In the RE-LY® Trial, median (10th to 90th percentile) trough aPTT in adult patients receiving the PRADAXA 150-mg dose was 52 (40 to 76) seconds1

The degree of anticoagulant activity can also be assessed by the ECT. This test is a more specific measure of the effect of dabigatran than aPTT1

Average time course for effects of dabigatran on aPTT in adult patients with various degrees of renal impairment*†

Graph Showing aPTT Levels Over Time for Different PRADAXA Doses Based on CrCl Levels
Graph Showing aPTT Levels Over Time for Different PRADAXA Doses Based on CrCl Levels

While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, curves in the aPTT time course can be used to estimate time to reach a particular level of aPTT recovery—even when time since the last dose of PRADAXA is not precisely known1

  • Plasma concentration levels decline relatively quickly following discontinuation in patients with normal renal function2

aPTT = activated partial thromboplastin time

INR = international normalized ratio

P-gp = P-glycoprotein

  • *
    Curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT.1
  • †
    Simulations based on PK data from a study in subjects with renal impairment and PK/aPTT relationships derived from the RE‑LY® Trial; aPTT prolongation in RE‑LY® was measured centrally in citrate plasma using PTT Reagent (Roche Diagnostics GmbH, Mannheim, Germany). There may be quantitative differences between various established methods for aPTT assessment.1

References:

  1. Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 

  2. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116-1127.

INDICATIONS AND USAGE

Pradaxa® (dabigatran etexilate) Capsules is indicated:

  • to reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation;
  • for the treatment of deep venous thrombosis and pulmonary embolism in adult patients who have been treated with a parenteral anticoagulant for 5-10 days;
  • to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in adult patients who have been previously treated;
  • for the prophylaxis of deep vein thrombosis and pulmonary embolism in adult patients who have undergone hip replacement surgery.
IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

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

(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 anti-inflammatory 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

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 who are or will be anticoagulated.

CONTRAINDICATIONS

PRADAXA is contraindicated in patients with:

  • active pathological bleeding;

  • history of a serious hypersensitivity reaction to dabigatran, dabigatran etexilate, or to one of the excipients of PRADAXA (e.g., anaphylactic reaction or anaphylactic shock);

  • mechanical prosthetic heart valve

WARNINGS & 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 Capsules is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart PRADAXA Capsules 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 Capsules in patients with active pathological bleeding.

  • Risk factors for bleeding include concomitant use of medications 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: In adults, a specific reversal agent (idarucizumab) for PRADAXA 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 clinical experience for hemodialysis as a treatment for bleeding is limited. Prothrombin complex concentrates or recombinant Factor VIIa may be considered but their use has not been evaluated. Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity. Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used.

Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves

The use of PRADAXA is contraindicated in all patients with mechanical prosthetic valves due to a higher risk for thromboembolic events, especially in the post-operative period, and an excess of major bleeding for PRADAXA vs. warfarin. Use of PRADAXA for the prophylaxis of thromboembolic events in patients with AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure

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 major independent factors in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.

Reduction of Risk of Stroke/Systemic Embolism in NVAF in Adult Patients.

  • For patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of PRADAXA Capsules to 75 mg twice daily when dronedarone or systemic ketoconazole is co-administered with PRADAXA.
  • For patients with severe renal impairment (CrCl 15-30 mL/min), avoid concomitant use of PRADAXA Capsules and P-gp inhibitors.

Treatment and Reduction in the Risk of Recurrence of DVT/PE & Prophylaxis of DVT/PE Following Hip Replacement Surgery in Adult Patients.

  • For patients with CrCl <50 mL/min, avoid use of PRADAXA Capsules and concomitant P-gp inhibitors.

Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

There is an increased risk of thrombosis in patients with triple-positive antiphospholipid syndrome. PRADAXA use is not recommended.

ADVERSE REACTIONS

The most common adverse reactions (>15%) reported with PRADAXA are gastrointestinal adverse reactions and bleeding.

Other Measures Evaluated

In NVAF patients, a higher rate of clinical MI was reported in patients who received PRADAXA (0.7/100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

USE IN SPECIFIC POPULATIONS

Pregnancy: The limited available data on PRADAXA use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes.

Lactation: Breastfeeding is not recommended.

Females and Males of Reproductive Potential: Discuss pregnancy planning with females of reproductive potential requiring anticoagulation. Assess the risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, in females of reproductive potential and those with abnormal uterine bleeding.

Pediatric Use: The safety and effectiveness of PRADAXA Capsules for the treatment and the reduction in risk of recurrence of venous thromboembolism have been established in pediatric patients 8 to less than 18 years of age. Other age-appropriate pediatric dosage forms of dabigatran etexilate are available for pediatric patients less than 8 years of age for these indications. Safety and effectiveness of PRADAXA Capsules have not been established in pediatric patients with non-valvular atrial fibrillation or those who have undergone hip replacement surgery.

Geriatric: Risk of bleeding increases with age.

CL-PX-100063 06.28.2021

Please see full Prescribing Information, including boxed WARNING and Medication Guide.