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Pradaxa (dabigatran etexilate mesylate) - 4 indications
Scroll down for additional information on each indication:
- to reduce the risk of stroke and embolism in patients with non-valvular atrial fibrillation; approved October 2010
- for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients treated with a parenteral anticoagulant for five to 10 days and to reduce the risk of recurrent DVT and PE in patients who have been previously treated; approved April 2014
- for the prophylaxis of DVT and PE after hip replacement surgery; approved November 2015
- for the treatment of venous thromboembolic events (VTE) in pediatric patients 8 to less than 18 years of age who have been treated with a parenteral anticoagulant for at least 5 days and to reduce the risk of recurrence of VTE in pediatric patients 8 to less than 18 years of age who have been previously treated; approved June 2021
General Information
Pradaxa (dabigatran etexilate mesylate) is a competitive, direct thrombin inhibitor. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.
Pradaxa is specifically indicated for the following:
- to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation
- for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in adult patients who have been treated with a parenteral anticoagulant for 5-10 days and to reduce the risk of recurrence of DVT and PE in adult patients who have been previously treated
- for the prophylaxis of DVT and PE in adult patients who have undergone hip replacement surgery
- for the treatment of venous thromboembolic events (VTE) in pediatric patients 8 to less than 18 years of age who have been treated with a parenteral anticoagulant for at least 5 days and to reduce the risk of recurrence of VTE in pediatric patients 8 to less than 18 years of age who have been previously treated.
Pradaxa is supplied as a capsule for oral administration. Scroll down for the recommended dosing/administration for each indication.
Mechanism of Action
Pradaxa (dabigatran etexilate mesylate) is a competitive, direct thrombin inhibitor. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.
Side Effects
Adverse events associated with the use of Pradaxa may I nclude, but are not limited to, the following:
- bleeding
- gastrointestinal events (dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea)
The Pradaxa drug label comes with the following Black Box Warning: PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS: Premature discontinuation of any oral anticoagulant, including Pradaxa, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if Pradaxa is discontinued for a reason other than pathological bleeding or completion of a course of therapy. 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. Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently. Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated.
Indication 1 - to reduce the risk of stroke and embolism in patients with non-valvular atrial fibrillation
approved October 2010
Dosing/Administration
For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of Pradaxa Capsules is 150 mg taken orally, twice daily. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose of Pradaxa Capsules is 75 mg twice daily. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.
Clinical Trial Results
The FDA approval of Pradaxa was based on a multi-center, multinational, randomized parallel group trial dubbed RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy). The trial compared two blinded doses of Pradaxa (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3). A total of 18,113 patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation were enrolled. All had one or more of the following additional risk factors: previous stroke, transient ischemic attack (TIA), or systemic embolism; left ventricular ejection fraction <40%; symptomatic heart failure, older than 75 years and older than 65 years and one of the following: diabetes mellitus, coronary artery disease (CAD), or hypertension. The primary objective of this study was to determine if Pradaxa was non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism. Pradaxa 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism when compared to warfarin and to Pradaxa 110 mg twice daily (p0.004). Pradaxa 150 mg twice daily significantly reduced both ischemic and hemorrhagic strokes relative to warfarin.
Indication 2 - for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients treated with a parenteral anticoagulant for five to 10 days and to reduce the risk of recurrent DVT and PE in patients who have been previously treated
approved April 2014
Dosing/Administration
Treatment:
- For patients with CrCl >30 mL/min, the recommended dose of Pradaxa Capsules is 150 mg taken orally, twice daily, after 5-10 days of parenteral anticoagulation. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.
Risk Reduction:
- For patients with CrCl >30 mL/min, the recommended dose of Pradaxa Capsules is 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.
Clinical Trial Results
In the randomized, parallel group, double-blind trials, RE-COVER and RE-COVER II, patients with deep vein thrombosis and pulmonary embolism received Pradaxa Capsules 150 mg twice daily or warfarin (dosed to target INR of 2 to 3) following initial treatment with an approved parenteral anticoagulant for 5 to 10 days. In studies RE-COVER and RE-COVER II, the protocol specified non-inferiority margin for the hazard ratio was derived based on the upper limit of the 95% confidence interval of the historical warfarin effect. Pradaxa Capsules was demonstrated to be non-inferior to warfarin (dosed to target INR of 2 to 3) based on the primary composite endpoint (fatal PE or symptomatic non-fatal PE and/or DVT) and retains at least 66.9% (RE-COVER) and 63.9% (RE-COVER II) of the historical warfarin effect, respectively.
Indication 3 - for the prophylaxis of DVT and PE after hip replacement surgery
approved November 2015
Dosing/Administration
For patients with CrCl >30 mL/min, the recommended dose of Pradaxa Capsules is 110 mg taken orally 1-4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28-35 days. If Pradaxa is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.
Clinical Trial Results
In the randomized, parallel-group, double-blind, non-inferiority trials, RE-NOVATE and RE-NOVATE II patients received Pradaxa Capsules 75 mg orally 1-4 hours after surgery followed by 150 mg daily (RE-NOVATE), Pradaxa Capsules 110 mg orally 1-4 hours after surgery followed by 220 mg daily (RE-NOVATE and RE-NOVATE II) or subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery (RE-NOVATE and RE-NOVATE II) for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip replacement surgery. For efficacy evaluation all patients were to have bilateral venography of the lower extremities at 3 days after last dose of study drug unless an endpoint event had occurred earlier in the study. In the primary efficacy analysis, Pradaxa Capsules 110 mg orally 1-4 hours after surgery followed by 220 mg daily was non-inferior to enoxaparin 40 mg once daily in a composite endpoint of confirmed VTE (proximal or distal DVT on venogram, confirmed symptomatic DVT, or confirmed PE) and all cause death during the treatment period.
Indication 4 - for the treatment of venous thromboembolic events (VTE) in pediatric patients 8 to less than 18 years of age who have been treated with a parenteral anticoagulant for at least 5 days and to reduce the risk of recurrence of VTE in pediatric patients 8 to less than 18 years of age who have been previously treated
approved June 2021
Dosing/Administration
Pradaxa Capsules is dosed orally twice daily, one dose in the morning and one dose in the evening, at approximately the same time every day. The dosing interval should be as close to 12 hours as possible. The recommended dose of Pradaxa Capsules for the treatment of or reducing the risk of VTE in pediatric patients 8 to less than 18 years of age is based on the patient’s actual weight. Administer Pradaxa twice daily. Adjust the dose according to actual weight as treatment progresses.
Clinical Trial Results
The DIVERSITY study was conducted to demonstrate the efficacy and safety of Pradaxa compared to standard of care (SOC) for the treatment of venous thromboembolism (VTE) in pediatric patients from birth to less than 18 years of age. The study was designed as an open-label, randomized, parallel-group, noninferiority study. Patients enrolled were randomized according to a 2:1 scheme to either an age-appropriate formulation (capsules, oral pellets, or oral solution) of Pradaxa (doses adjusted for age and weight) after at least 5 days and no longer than 21 days of treatment with a parenteral anticoagulant, or to SOC comprised of low molecular weight heparins (LMWH) or vitamin K antagonists (VKA) or fondaparinux. For patients on Pradaxa, drug concentration was determined prior to the 7th dose and a single titration was permitted to achieve drug target levels of 50-250 ng/mL. Inability to achieve target, after one up-titration, resulted in premature termination of study drug in 12 patients (6.8%). The efficacy of Pradaxa was established based on a composite endpoint of patients with complete thrombus resolution, freedom from recurrent venous thromboembolic event, and freedom from mortality related to venous thromboembolic event (composite primary endpoint). Of the 267 randomized patients, 81 patients (45.8%) in the Pradaxa group and 38 patients (42.2%) in the SOC group met the criteria for the composite primary endpoint. The corresponding rate difference and 95% CI was -0.038 (-0.161, 0.086) and thus demonstrated non-inferiority of Pradaxa to SOC, since the upper bound of the 95% CI was lower than the predefined non-inferiority margin of 20%.