These highlights do not include all the information needed to use PRADAXA safely and effectively. See full prescribing information for PRADAXA. PRADAXA� (dabigatran etexilate mesylate) capsules for oral use Initial U.S. Approval: 2010
PRADAXA Information
Product Code 21695-899 Company Name Boehringer Ingelheim Pharmaceuticals Inc. Dosage From CAPSULE Strength 150 mg Active Ingredient dabigatran etexilate mesylate
Pradaxa (Dabigatran etexilate mesylate) Indications And Usage
Pradaxa (Dabigatran etexilate mesylate) is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
Pradaxa (Dabigatran etexilate mesylate) Dosage And Administration
For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of Pradaxa (Dabigatran etexilate mesylate) is 150 mg taken orally, twice daily, with or without food. For patients with CrCl 15-30 mL/min, the recommended dose is 75 mg twice daily . Dosing recommendations for patients with a CrCL
Instruct patients to swallow the capsules whole. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure .
If a dose of Pradaxa (Dabigatran etexilate mesylate) is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of Pradaxa (Dabigatran etexilate mesylate) should not be doubled to make up for a missed dose.
When converting patients from warfarin therapy to Pradaxa (Dabigatran etexilate mesylate) , discontinue warfarin and start Pradaxa (Dabigatran etexilate mesylate) when the international normalized ratio (INR) is below 2.0.
When converting from Pradaxa (Dabigatran etexilate mesylate) to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:
Because Pradaxa (Dabigatran etexilate mesylate) can contribute to an elevated INR, the INR will better reflect warfarin’s effect after Pradaxa (Dabigatran etexilate mesylate) has been stopped for at least 2 days.
For patients currently receiving a parenteral anticoagulant, start Pradaxa (Dabigatran etexilate mesylate) 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 patients currently taking Pradaxa (Dabigatran etexilate mesylate) , wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl
If possible, discontinue Pradaxa (Dabigatran etexilate mesylate) 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl
If surgery cannot be delayed, there is an increased risk of bleeding . This risk of bleeding should be weighed against the urgency of intervention . Bleeding risk can be assessed by the ecarin clotting time (ECT). This test is a better marker of the anticoagulant activity of dabigatran than activated partial thromboplastin time (aPTT), prothrombin time (PT)/INR, or thrombin time (TT). If ECT is not available, the aPTT test provides an approximation of Pradaxa (Dabigatran etexilate mesylate) ’s anticoagulant activity .
Pradaxa (Dabigatran etexilate mesylate) Dosage Forms And Strengths
Capsules with a light blue opaque cap imprinted in black with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted in black with "R150" (150 mg) or "R75" (75 mg).
Pradaxa (Dabigatran etexilate mesylate) Contraindications
Pradaxa (Dabigatran etexilate mesylate) is contraindicated in patients with:
Pradaxa (Dabigatran etexilate mesylate) Warnings And Precautions
Pradaxa (Dabigatran etexilate mesylate) increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Risk factors for bleeding include the use of drugs that increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs) and labor and delivery. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue Pradaxa (Dabigatran etexilate mesylate) in patients with active pathological bleeding.
In the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study, a life-threatening bleed (bleeding that met one or more of the following criteria: fatal, symptomatic intracranial, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention) occurred at an annualized rate of 1.5% and 1.8% for Pradaxa (Dabigatran etexilate mesylate) 150 mg and warfarin, respectively .
The concomitant use of Pradaxa (Dabigatran etexilate mesylate) with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided .
P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin do not require dose adjustments. These results should not be extrapolated to other P-gp inhibitors .
Pradaxa (Dabigatran etexilate mesylate) Drug Interactions
The concomitant use of Pradaxa (Dabigatran etexilate mesylate) with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided .
P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin do not require dose adjustments. These results should not be extrapolated to other P-gp inhibitors .
Pradaxa (Dabigatran etexilate mesylate) Use In Specific Populations
Safety and effectiveness of Pradaxa (Dabigatran etexilate mesylate) during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using Pradaxa (Dabigatran etexilate mesylate) in this setting .
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).
Pradaxa (Dabigatran etexilate mesylate) Overdosage
Accidental overdose may lead to hemorrhagic complications. There is no antidote to dabigatran etexilate or dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with Pradaxa (Dabigatran etexilate mesylate) , and investigate the source of bleeding. Dabigatran is primarily excreted in the urine; therefore, maintain adequate diuresis. Dabigatran can be dialyzed (protein binding is low), with the removal of about 60% of drug over 2 to 3 hours; however, data supporting this approach are limited. Consider surgical hemostasis or the transfusion of fresh frozen plasma or red blood cells. There is some experimental evidence to support the role of activated prothrombin complex concentrates (e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X; however, their usefulness in clinical settings has not been established. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used. Measurement of aPTT or ECT may help guide therapy .
Pradaxa (Dabigatran etexilate mesylate) Description
The chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor, is β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The empirical formula is CHNO • CHOS and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is:
Dabigatran etexilate mesylate is a yellow-white to yellow powder. A saturated solution in pure water has a solubility of 1.8 mg/mL. It is freely soluble in methanol, slightly soluble in ethanol, and sparingly soluble in isopropanol.
The 150 mg capsule for oral administration contains 172.95 mg dabigatran etexilate mesylate, which is equivalent to 150 mg of dabigatran etexilate, and the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc, and tartaric acid. The capsule shell is composed of carrageenan, FD&C Blue No. 2, FD&C Yellow No. 6, hypromellose, potassium chloride, titanium dioxide, and black edible ink. The 75 mg capsule contains 86.48 mg dabigatran etexilate mesylate, equivalent to 75 mg dabigatran etexilate, and is otherwise similar to the 150 mg capsule.
Pradaxa (Dabigatran etexilate mesylate) Clinical Studies
The clinical evidence for the efficacy of Pradaxa (Dabigatran etexilate mesylate) was derived from RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy), a multi-center, multi-national, randomized parallel group trial comparing two blinded doses of Pradaxa (Dabigatran etexilate mesylate) (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation and one or more of the following additional risk factors:
The primary objective of this study was to determine if Pradaxa (Dabigatran etexilate mesylate) was non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism. The study was designed to ensure that Pradaxa (Dabigatran etexilate mesylate) preserved more than 50% of warfarin’s effect as established by previous randomized, placebo-controlled trials of warfarin in atrial fibrillation. Statistical superiority was also analyzed.
A total of 18,113 patients were randomized and followed for a median of 2 years. The patient’s mean age was 71.5 years and the mean CHADS score was 2.1. The patient population was 64% male, 70% Caucasian, 16% Asian, and 1% black. Twenty percent of patients had a history of a stroke or TIA and 50% were Vitamin K antagonist (VKA) naïve, defined as less than 2 months total lifetime exposure to a VKA. Thirty-two percent of the population had never been exposed to a VKA. Concomitant diseases of patients in this trial included hypertension 79%, diabetes 23%, and CAD 28%. At baseline, 40% of patients were on aspirin and 6% were on clopidogrel. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2 to 3) was 64%; the mean percentages of time INR measurements were greater than 4 or less than 1.5 were 2% and 5%, respectively.
Relative to warfarin and to Pradaxa (Dabigatran etexilate mesylate) 110 mg twice daily, Pradaxa (Dabigatran etexilate mesylate) 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism (see Table 4 and Figure 1).
Figure 1 Kaplan-Meier Curve Estimate of Time to First Stroke or Systemic Embolism
The contributions of the components of the composite endpoint, including stroke by subtype, are shown in Table 5. The treatment effect was primarily a reduction in stroke. Pradaxa (Dabigatran etexilate mesylate) 150 mg twice daily significantly reduced both ischemic and hemorrhagic strokes relative to warfarin.
The efficacy of Pradaxa (Dabigatran etexilate mesylate) 150 mg twice daily was generally consistent across major subgroups (see Figure 2).
Figure 2 Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics
Centers were ranked post hoc by the percentage of time that warfarin-treated patients were in therapeutic range (INR 2 to 3). Findings for stroke/systemic embolism, all-cause mortality, and major bleeds are shown for centers above and below the median level of INR control in Table 6. The benefits of Pradaxa (Dabigatran etexilate mesylate) 150 mg relative to warfarin were most apparent in patients enrolled at centers with INR control below the median.
The risk of myocardial infarction was numerically greater in patients who received Pradaxa (Dabigatran etexilate mesylate) (1.5% for 150 mg dose) than in those who received warfarin (1.1%).
Pradaxa (Dabigatran etexilate mesylate) How Supplied/storage And Handling
Pradaxa (Dabigatran etexilate mesylate) 75 mg capsules have a light blue opaque cap imprinted with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted with "R75". The color of the imprinting is black. The capsules are supplied in the packages listed:
Pradaxa (Dabigatran etexilate mesylate) 150 mg capsules have a light blue opaque cap imprinted with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted with "R150". The color of the imprinting is black. The capsules are supplied in the packages listed:
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Once opened, the product must be used within 30 days. Keep the bottle tightly closed. Store in the original package to protect from moisture.
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Store in the original package to protect from moisture.
Keep out of the reach of children.
Pradaxa (Dabigatran etexilate mesylate) Patient Counseling Information
Inform patients that they may bleed more easily, may bleed longer, and should call their health care provider for any signs or symptoms of bleeding.
Instruct patients to seek emergency care right away if they have any of the following, which may be a sign or symptom of serious bleeding:
Instruct patients to call their health care provider or to get prompt medical attention if they experience any signs or symptoms of bleeding:
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA
Copyright 2011 Boehringer Ingelheim Pharmaceuticals, Inc. ALL RIGHTS RESERVED.
