Pradaxa - Drug Monograph

Introduction

Pradaxa (dabigatran etexilate) is an oral direct thrombin inhibitor anticoagulant approved by the FDA in 2010. It represents a significant advancement in anticoagulation therapy as the first novel oral anticoagulant developed as an alternative to warfarin for stroke prevention in non-valvular atrial fibrillation. Unlike warfarin, Pradaxa does not require routine coagulation monitoring and has fewer food and drug interactions.

Mechanism of Action

Dabigatran etexilate is a prodrug that is converted to its active form, dabigatran, by esterase-catalyzed hydrolysis in plasma and liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor. Thrombin (serine protease factor IIa) plays a central role in the coagulation cascade by converting fibrinogen to fibrin and activating factors V, VIII, XI, and XIII. By binding to both free and clot-bound thrombin, dabigatran prevents thrombus development and extension.

Indications

• Reduction of risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation
• Treatment and reduction in the risk of recurrence of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with parenteral anticoagulants for 5-10 days
• Prophylaxis of DVT and PE in patients who have undergone hip replacement surgery
• Prevention of venous thromboembolic events in pediatric patients 8 years and older who have undergone orthopedic surgery

Dosage and Administration

• Non-valvular atrial fibrillation: 150 mg twice daily (reduce to 75 mg twice daily in patients with severe renal impairment CrCl 15-30 mL/min)
• DVT/PE treatment: 150 mg twice daily after 5-10 days of parenteral anticoagulation
• Hip replacement prophylaxis: 110 mg first day 1-4 hours after surgery, then 220 mg once daily

• Renal impairment: Dose adjustment required based on creatinine clearance
• Hepatic impairment: Not recommended in patients with hepatic impairment or liver disease expected to impact survival
• Geriatric: Consider renal function; no additional adjustment beyond renal dosing
• Pediatric: Weight-based dosing for approved indications

Pharmacokinetics

• Absorption: Absolute bioavailability approximately 6.5%; peak plasma concentrations reached within 1-2 hours; high-fat meal delays absorption but does not affect extent
• Distribution: Volume of distribution 50-70 L; 35% plasma protein bound
• Metabolism: Esterase-mediated hydrolysis to active dabigatran; not a substrate, inhibitor, or inducer of CYP450 enzymes
• Elimination: Primarily renal (85%); elimination half-life 12-17 hours in healthy subjects; prolonged in renal impairment

Contraindications

• Active pathological bleeding
• History of serious hypersensitivity reaction to dabigatran
• Mechanical prosthetic heart valves (increased risk of thromboembolism and bleeding)
• Triple-positive antiphospholipid syndrome (increased thrombotic risk)

Warnings and Precautions

• Risk of bleeding: Can cause serious and fatal bleeding; consider risk factors for bleeding
• Spinal/epidural hematoma risk: With neuraxial anesthesia; monitor for neurological symptoms
• Thrombotic events with premature discontinuation: Increased risk with abrupt discontinuation
• Renal impairment: Increased exposure and bleeding risk; monitor renal function periodically
• Gastrointestinal adverse reactions: Higher rate of GI bleeding compared to warfarin in some studies
• PGRN laboratory test interference: Dabigatran may cause overestimation of INR

Drug Interactions

• Strong P-gp inducers: Rifampin reduces dabigatran exposure; avoid concomitant use
• P-gp inhibitors in renal impairment: Dronedarone, ketoconazole, cyclosporine, clarithromycin increase exposure in patients with CrCl <50 mL/min
• Anticoagulants/antiplatelets: Increased bleeding risk with warfarin, heparin, NSAIDs, aspirin, clopidogrel
• Thrombolytics: Increased bleeding risk

Adverse Effects

• Gastrointestinal: Dyspepsia, abdominal pain, nausea, diarrhea
• Bleeding: Minor bleeding episodes, bruising
• Other: Rash, pruritus

• Major bleeding (GI, intracranial)
• Hypersensitivity reactions (anaphylaxis)
• Spinal/epidural hematoma
• Thrombotic events with premature discontinuation

Monitoring Parameters

• Baseline: Renal function (serum creatinine, CrCl), CBC, liver function tests
• Ongoing: Signs/symptoms of bleeding, renal function every 6-12 months or when clinically indicated
• Special situations: Preoperatively (hold appropriately), with concomitant P-gp inhibitors, with changing renal function
• No routine coagulation monitoring required (aPTT can provide qualitative assessment if needed)

Patient Education

• Take exactly as prescribed; do not miss doses
• Swallow capsule whole; do not break, chew, or empty contents
• Report any signs of bleeding (unusual bruising, pink/brown urine, red/black stools, coughing blood, headaches, dizziness)
• Inform all healthcare providers about Pradaxa use, especially before procedures
• Do not stop taking without medical advice due to stroke risk
• Use caution with OTC medications that may increase bleeding risk (NSAIDs, aspirin)
• Store in original bottle to protect from moisture; discard after 4 months once opened

References

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. 2. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2023. 3. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. J Am Coll Cardiol. 2019;74(1):104-132. 4. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352. 5. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015;17(10):1467-1507.