Dabigatran

{{drugbox | | IUPAC_name = Ethyl 3-{[(2-{[(4-{N'-[(hexyloxy)carbonyl] carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H- benzimidazol-5-yl)carbonyl] (2-pyridinyl)amino}propanoate | image = Dabigatran etexilate.png | width = 135px | CAS_number = 211915-06-9 | CAS_supplemental = 211914-51-1 | ATC_prefix = | ATC_suffix = | ATC_supplemental= | PubChem = 6445226 | DrugBank = | chemical_formula = | C=34 | H=41 | N=7 | I= | Br= | Cl= | F= | O=5 | P= | S= | Se= | Na= | charge= | molecular_weight = 627.734 (471.511 without etexilate) | specific_rotation = | sec_combustion = | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_UK = | legal_US = | legal_status = | dependency_liability = unknown | routes_of_administration = oral }} Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]. Dr. Gibson has received research grant support from all major manufacturers of antithrombins and antiplatelets. For full disclosure information click here.

Synonyms and keywords: Pradaxa, rendix

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or the FDA Medwatch site.

Overview

Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications, for some of which it may replace warfarin as the preferred anticoagulant. It is orally administered as the prodrug dabigatran etexilate (planned trade names Rendix and Pradaxa). It was developed by pharmaceutical company Boehringer-Ingelheim.

Development

Dabigatran (then compound BIBR 953) was discovered from a panel of chemicals with similar structure to benzamidine-based thrombin inhibitor α-NAPAP (N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of various serine proteases, specifically thrombin but also trypsin. Addition of a hydrophobic side chain led to the orally absorbed prodrug BIBR 1048 (dabigatran etexilate).
Phase 3 clinical trials are ongoing in treatment and prevention of secondary venous thromboembolism (VTE) in post-operative orthopedic patients (expected results by Oct 2007); long-term prophylaxis in acute coronary syndrome and stroke patients and symptomatic VTE because of various causes (expected results by 2009-2010).

Indications

Dabigatran is indicated in the United States for the treatment of non-valvular atrial fibrillation based upon the results of the RE-LY trial.

Dosing

United States

The dose approved for use in atrial fibrillation in the United States is:

• 150 mg orally twice a day (PO bid) in patients with a CrCl > 30 ml/min
• 75 mg orally twice a day (PO bid) in patients with renal insufficiency (CrCl 15-30 ml/min).

Patients should be instructed not to chew, break, or open capsules. If a dose of PRADAXA 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 should not be doubled to make up for a missed dose.

Canada, Japan and Most of World

In most of the world, Pradaxa is expected to also be approved at the 110 mg dose.

Storage Conditions

• PRADAXA should be stored at room temperature between 59 and 86 degrees F (15 to 30 degrees C).
• PRADAXA comes in a bottle or in a blister package.

The Drug is Potent for 4 months When Supplied in a Bottle

• Once the bottle is opened, PRADAXA should be used within a period of 4 months. Any unused PRADAXA after 4 months should be safely thrown away if it is packaged in a bottle. Blister package have a longer half life.

Converting from or to Warfarin

When converting patients from warfarin therapy to PRADAXA, discontinue warfarin and start PRADAXA when the international normalized ratio (INR) is below 2.0. When converting from PRADAXA to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:

• For CrCl >50 mL/min, start warfarin 3 days before discontinuing PRADAXA.
• For CrCl 31-50 mL/min, start warfarin 2 days before discontinuing PRADAXA.
• For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing PRADAXA.
• For CrCl <15 mL/min, no recommendations can be made.

Because PRADAXA can contribute to an elevated INR, the INR will better reflect warfarin’s effect after PRADAXA has been stopped for at least 2 days.

Converting from or to Parenteral Anticoagulants

For patients currently receiving a parenteral anticoagulant, 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 (e.g., intravenous unfractionated heparin). For patients currently taking PRADAXA, wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of PRADAXA before initiating treatment with a parenteral anticoagulant.

Monitoring

Unlike coumadin, no INR monitoring is required.

Surgery and Interventions

The best time to temporarily withhold Dabigatran before a surgery or an invasive procedure is dictated by two factors:

• The renal function of the patient
• The bleeding risk of the surgery.

Given the fact that Dabigatran is 80% renally excreted, renal function must be taken into consideration to decide when to stop Dabigatran preoperatively. In addition, the type of surgery and its associated risk of bleeding influence the decision on the optimal timing to stop Dabigatran. In surgeries with standard risk of bleeding, like hernia repair, Dabigatran should be stopped two to three half lives prior to the procedures allowing its level to drop to 25%. As for surgeries with high risk of bleeding where complete hemostasis may be required, as in major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, Dabigatran should be stopped four to five half lives before the surgery.

Dabigatran was found to have similar rates of perioperative bleeding and thrombotic complications to those of warfarin. Dabigatran has the advantages of having a predictable anticoagulation effect and a shorter half life allowing the patients to be four times more likely to undergo their surgeries or invasive procedures when needed on an urgent basis within two days of stopping Dabigatran.

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’s anticoagulant activity.

Shown below is a table summarizing the amended perioperative guidelines for management of Dabigatran for patients having surgery.

		Time to Stop Dabigatran Before a Surgery or a Procedure
Renal Function Impairement Creatinine Clearance (mL/min)	Estimated Half Life Range (hours)	High Risk for Bleeding	Standard Risk for Bleeding
Mild (≥50-80)	15 (12-18)	2-3 days	24 hours (2 doses)
Moderate (≥30 to <50)	18 (18-24)	4 days	At least 2 days (48 hours)
Severe (<50)	27 (>24)	>5 days	2-4 days

WARNINGS AND PRECAUTIONS

• Risk of bleeding: PRADAXA can cause serious and, sometimes, fatal bleeding. Promptly evaluate signs and symptoms of blood loss.
• Risk of ACS or MI
• Temporary discontinuation: Avoid lapses in therapy to minimize risk of stroke
• P-gp inducers and inhibitors: Avoid coadministration of rifampin with PRADAXA because of effects on dabigatran exposure

Risk of Bleeding

PRADAXA 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 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 150 mg and warfarin, respectively.

Risk of ACS or MI

The results of RE-LY study demonstrates that the use of dabigatran is significantly increases the risk of MI or ACS(dabigatran:1.19% vs control:0.79%; odds ratio [ORM-H]: 1.33; 95% CI, 1.03-1.71; P = 0.03. A meta analysis of seven trials(N = 30 514): 2 studies of stroke prophylaxis in atrial fibrillation, 1 in acute venous thromboembolism, 1 in ACS, and 3 of short-term prophylaxis of deep venous thrombosis demonstrated similar trends and were consistent using different methods and measures of association. Further investigations are required in assessing the cardiac risk of dabigatran in patients with high risk of ACS or MI.

Temporary Discontinuation of PRADAXA

Discontinuing anticoagulants, including PRADAXA, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Lapses in therapy should be avoided, and if anticoagulation with PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure

The concomitant use of PRADAXA 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 Pgp inhibitors.

Adverse Reactions

Gastrointestinal Adverse Reactions

Patients on PRADAXA 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs. 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).

Hypersensitivity Reactions

In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving PRADAXA.

Use in Specific Populations

Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at maximum recommended human dose [MRHD] of 300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation(gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat, it did not induce major malformations in rats or rabbits.

Labor and Delivery

Safety and effectiveness of PRADAXA during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using PRADAXA 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).

Nursing Mothers

It is not known whether dabigatran is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRADAXA is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of PRADAXA in pediatric patients has not been established.

Geriatric Use

Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.

Renal Impairment

No dose adjustment of PRADAXA is recommended in patients with mild or moderate renal impairment. Reduce the dose of PRADAXA in patients with severe renal impairment (CrCl 15-30 mL/min). Dosing recommendations for patients with CrCl <15 mL/min or on dialysis cannot be provided.

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, 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.

References

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