Prescription Drug Information: Dabigatran Etexilate (Page 2 of 8)

2.6 Converting from or to Warfarin

When converting patients from warfarin therapy to dabigatran etexilate capsules, discontinue warfarin and start dabigatran etexilate capsules when the INR is below 2.0.

When converting from dabigatran etexilate capsules to warfarin, adjust the starting time of warfarin as follows:

Adults
• For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing dabigatran etexilate capsules.
• For CrCl 30 to 50 mL/min, start warfarin 2 days before discontinuing dabigatran etexilate capsules.
• For CrCl 15 to 30 mL/min, start warfarin 1 day before discontinuing dabigatran etexilate capsules.
• For CrCl <15 mL/min, no recommendations can be made.

Because dabigatran etexilate capsules can increase INR, the INR will better reflect warfarin’s effect only after dabigatran etexilate capsules has been stopped for at least 2 days [see Clinical Pharmacology ( 12.2)].

Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.7 Converting from or to Parenteral Anticoagulants


For adult patients currently receiving a parenteral anticoagulant, start dabigatran etexilate capsules 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 (e.g., intravenous unfractionated heparin).
For adult patients currently taking dabigatran etexilate capsules wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of dabigatran etexilate capsules before initiating treatment with a parenteral anticoagulant [see Clinical Pharmacology ( 12.3)]. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.8 Discontinuation for Surgery and Other Interventions

If possible, discontinue dabigatran etexilate capsules in adults 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding. Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required [see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)].

If surgery cannot be delayed, there is an increased risk of bleeding [see Warnings and Precautions ( 5.2)]. This risk of bleeding should be weighed against the urgency of intervention [see Warnings and Precautions ( 5.1,5.3)]. Use a specific reversal agent (idarucizumab) in case of emergency surgery or urgent procedures when reversal of the anticoagulant effect of dabigatran is needed in adults. Efficacy and safety of idarucizumab have not been established in pediatric patients [see Warnings and Precautions ( 5.2)]. Refer to the idarucizumab prescribing information for additional information. Restart dabigatran etexilate capsules as soon as medically appropriate.

Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

3 DOSAGE FORMS AND STRENGTHS

150 mg capsules with a cream opaque cap / cream opaque body size ‘0’ HPMC capsules imprinted with ‘H’ on cap and ‘D11’ on body with black ink, filled with mixture of off white to yellowish white pellets.

75 mg capsules with a cream opaque cap / cream opaque body size ‘2’ HPMC capsules imprinted with ‘H’ on cap and ‘D10’ on body with black ink, filled with mixture of off white to yellowish white pellets.

4 CONTRAINDICATIONS

Dabigatran etexilate capsules are contraindicated in patients with:
• Active pathological bleeding [see Warnings and Precautions ( 5.2) and Adverse Reactions ( 6.1)]
• History of a serious hypersensitivity reaction to dabigatran, dabigatran etexilate, or to one of the excipients of the product (e.g., anaphylactic reaction or anaphylactic shock) [see Adverse Reactions ( 6.1)] • Mechanical prosthetic heart valve [see Warnings and Precautions ( 5.4)]

5 WARNINGS AND PRECAUTIONS

5.1 Increased Risk of Thrombotic Events after Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including dabigatran etexilate capsules, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If dabigatran etexilate capsules are discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart dabigatran etexilate capsules as soon as medically appropriate [see Dosage and Administration ( 2.6, 2.7, 2.8)].

5.2 Risk of Bleeding

Dabigatran etexilate capsules 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 dabigatran etexilate capsules in patients with active pathological bleeding [see Dosage and Administration ( 2.4)].

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). Dabigatran etexilate capsules anticoagulant activity and half-life are increased in patients with renal impairment [see Clinical Pharmacology ( 12.2)].

Reversal of Anticoagulant Effect:
In adults, a specific reversal agent (idarucizumab) for dabigatran etexilate is available when reversal of the anticoagulant effect of dabigatran is needed:
• For emergency surgery/urgent procedures
• In life-threatening or uncontrolled bleeding

In pediatric patients, the efficacy and safety of idarucizumab have not been established.

Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as a treatment for bleeding is limited [see Overdosage ( 10)]. 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.

5.3 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 etexilate and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dabigatran [see Clinical Pharmacology ( 12.3)]. 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.

5.4 Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves


The safety and efficacy of dabigatran etexilate capsules in adult 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 mg, 220 mg, or 300 mg of dabigatran etexilate capsules 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 dabigatran etexilate capsules treatment arm as compared to the warfarin treatment arm. These bleeding and thromboembolic events were seen both in patients who were initiated on dabigatran etexilate capsules postoperatively 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 dabigatran etexilate capsules are contraindicated in all patients with mechanical prosthetic valves [see Contraindications ( 4)]. The use of dabigatran etexilate capsules 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.

5.5 Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure

The concomitant use of dabigatran etexilate capsules with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology ( 12.3)].

P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology ( 12.3)]. 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 in Adult Patients
Reduce the dose of dabigatran etexilate capsules to 75 mg twice daily when dronedarone or systemic ketoconazole is co-administered with dabigatran etexilate capsules in patients with moderate renal impairment (CrCl 30 to 50 mL/min). Avoid use of dabigatran etexilate capsules and P-gp inhibitors in patients with severe renal impairment (CrCl 15 to 30 mL/min) [see Drug Interactions (7.1) and Use in Specific Populations ( 8.6)].

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients
Avoid use of dabigatran etexilate capsules and concomitant P-gp inhibitors in patients with CrCl<50 mL/min [see Drug Interactions ( 7.2) and Use in Specific Populations ( 8.6)].

Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

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