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Dabigatran Etexilate Mesylate

Pronunciation

Pronunciation: DA-bi-GAT-ran e-TEX-i-late MES-i-late
Class: Thrombin inhibitor

Trade Names

Pradaxa
- Capsules, oral 75 mg
- Capsules, oral 150 mg

Pharmacology

Binds to thrombin, blocking the thrombogenic activity of thrombin, thereby preventing the development of a thrombus.

Slideshow: Atrial Fibrillation - Stroke Prevention Guidelines & Treatment Options

Pharmacokinetics

Absorption

Absolute bioavailability is approximately 3% to 7%. T max is 1 h. Oral bioavailability increases by 75% when the pellets are taken without the capsule shell compared with the intact capsule formulation. Coadministration with a high-fat meal delays T max by 2 h but has no effect on the bioavailability of dabigatran.

Distribution

35% bound to plasma proteins. Vd is 50 to 70 L.

Metabolism

The cleavage of dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominate metabolic reaction. Dabigatran is subject to conjugation forming 4 different active acyl glucuronides (1-, 2-, 3-, and 4-O-acylglucuronide).

Elimination

Eliminated primarily in the urine. Half-life is 12 to 17 h.

Special Populations

Renal Function Impairment

Exposure to dabigatran increases with the severity of renal impairment. AUC increases 1.5, 3.2, and 6.3 times in patients with mild, moderate, and severe renal impairment, respectively.

Hepatic Function Impairment

Administration to patients with moderate hepatic impairment (Child-Pugh class B) showed a large intersubject variability but no evidence of a consistent change in exposure or pharmacodynamics.

Indications and Usage

To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Contraindications

Active pathological bleeding; history of a serious hypersensitivity reaction to dabigatran.

Dosage and Administration

Adults

PO 150 mg twice daily.

Conversion
Adults Parenteral anticoagulant

PO For patients currently receiving a parenteral anticoagulant, start dabigatran 0 to 2 h 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. For patients taking dabigatran, wait 12 h (CrCl 30 mL/min or more) or 24 h (CrCl less than 30 mL/min) after the last dose of dabigatran before initiating treatment with a parenteral anticoagulant.

Warfarin

PO When converting patients from warfarin to dabigatran, discontinue warfarin and start dabigatran when the INR is below 2. When converting from dabigatran to warfarin, adjust the starting time of warfarin based on CrCl. For CrCl 50 mL/min or more, start warfarin 3 days before discontinuing dabigatran; for CrCl 31 to 50 mL/min, start warfarin 2 days before discontinuing dabigatran; for CrCl 15 to 30 mL/min, start warfarin 1 day before discontinuing dabigatran; for CrCl less than 15 mL/min, no recommendation can be made.

Renal Function Impairment
Adults CrCl 30 to 50 mL/min

PO 75 mg twice daily in patients taking concomitant dronedarone or ketoconazole.

CrCl 15 to 30 mL/min

PO 75 mg twice daily.

CrCl less than 15 mL/min

Dosing recommendation cannot be provided.

General Advice

  • The capsules should be swallowed whole. Advise patients not to break, chew, or empty the capsule's contents in food or beverages.
  • May be taken with or without food.
  • If a dose is not taken at the scheduled time, it 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 h before the next scheduled dose. Advise patient to not double the dose to make up for a missed dose.
  • If possible, discontinue dabigatran 1 to 2 days (CrCl 50 mL/min or more) or 3 to 5 days (CrCl less than 50 mL/min) before invasive or surgical procedures. Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port.
  • Discontinuing dabigatran places the patient at an increased risk of stroke. Minimize lapses in therapy; if dabigatran must be temporarily discontinued for any reason, restart therapy as soon as possible.

Storage/Stability

Store between 59° and 86°F. Once the bottle is opened, use within 4 mo. Store in original package to protect from moisture.

Drug Interactions

Amiodarone, clopidogrel, ketoconazole, quinidine, verapamil

May increase dabigatran AUC and C max . No important change in dabigatran trough concentration was observed with dabigatran and amiodarone or verapamil coadministration. Consider reducing the dabigatran dose to 75 mg twice daily when systemic ketoconazole is coadministered with dabigatran in patients with moderate renal impairment (CrCl 30 to 50 mL/min).

Dronedarone

Dabigatran exposure is higher when administered with dronedarone compared with administration alone. Use with caution. Consider reducing the dabigatran dosage to 75 mg twice daily when dronedarone is coadministered with dabigatran in patients with moderate renal impairment (CrCl 30 to 50 mL/min).

Drugs that increase the risk of bleeding (eg, antiplatelet agents [eg, clopidogrel, ticlopidine], aspirin, fibrinolytic therapy [eg, alteplase], fondaparinux, glycoprotein IIb/IIIa inhibitors [eg, abciximab], heparin and heparin derivatives, long-term use of NSAIDs [eg, ibuprofen], rivaroxaban, thrombin inhibitors [eg, bivalirudin], warfarin)

The risk of severe and sometimes fatal bleeding may be increased. Monitor for any signs or symptoms of blood loss (eg, drop in Hgb, hypotension). Discontinue dabigatran in patients with active pathologic bleeding.

Rifamycins (eg, rifampin)

Dabigatran exposure may be reduced, decreasing the efficacy. Avoid concurrent use of rifampin.

St. John's wort

Pharmacologic effects and plasma concentrations of dabigatran may be decreased. Coadministration is not recommended.

Adverse Reactions

Cardiovascular

Intracranial hemorrhage.

GI

Dyspepsia (eg, abdominal discomfort, abdominal pain, abdominal pain upper, epigastric discomfort), gastritis-like symptoms (eg, gastroesophageal reflux disease, erosive gastritis, esophagitis, gastric hemorrhage, GI ulcer, hemorrhagic erosive gastritis, hemorrhagic gastritis) (35%); GI bleed (6%); major GI bleed (2%).

Miscellaneous

Bleeding (17%); major bleed (3%); life-threatening bleed (2%).

Precautions

Monitor

Monitor for signs of bleeding throughout therapy. Assess renal function prior to initiation of therapy and periodically during therapy as clinically indicated (ie, more frequently in situations that may be associated with a decline in renal function). Generally the extent of anticoagulation does not need to be assessed. When necessary, use APTT or ecarin clotting time to assess anticoagulant activity.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

The risk of stroke and bleeding increases with age.

Renal Function

Anticoagulant activity and half-life of dabigatran are increased in patients with renal impairment. Adjust the dose in patients with severe renal impairment (CrCl 15 to 30 mL/min) and in patients with moderate renal impairment receiving concomitant P-glycoprotein inhibitors.

Bleeding

Dabigatran increases the risk of bleeding and can cause fatal bleeding. Discontinue in patients with active pathological bleeding.

Overdosage

Symptoms

Hemorrhagic complications.

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Advise patients to keep dabigatran in the original bottle to protect it from moisture. Advise patients not to put dabigatran in pill boxes or pill organizers. When more than 1 bottle is dispensed, instruct patients to open only 1 bottle at a time. Instruct patients to remove only 1 capsule from the opened bottle at the time of use. Advise patients that the bottle should be immediately and tightly closed.
  • Remind patients not to discontinue dabigatran without talking with their health care provider.
  • Advise patients not to chew or break the capsules before swallowing and not to open the capsules and take the pellets alone.
  • Advise patients that if they miss a dose, the dose should be taken as soon as possible on the same day; instruct them to skip the missed dose if it cannot be taken at least 6 h before the next scheduled dose. Instruct patients not to double the dose to make up for a missed dose.
  • Inform patients that they may bleed more easily or longer and to seek emergency care right away if they have any signs of serious bleeding (eg, coughing up blood; pink or brown urine; red or black, tarry stools; unusual bruising; vomiting blood that looks like coffee grounds).
  • Instruct patients to call their health care provider if they experience any signs or symptoms of bleeding (eg, bleeding from a cut that takes a long time to stop; headaches, dizziness, or weakness; menstrual bleeding or vaginal bleeding that is heavier than normal; pain, swelling, or discomfort of a joint; recurring nosebleeds; unusual bleeding from the gums).
  • Instruct patients to call their health care provider if they experience any signs or symptoms of dyspepsia or gastritis (eg, abdominal pain or discomfort, epigastric discomfort or gastric indigestion, upset stomach, burning, nausea).
  • Instruct patients to inform their health care provider that they are taking dabigatran before any invasive procedures (including dental procedures) are scheduled.
  • Ask patients to list all prescription medications, OTC medications, and dietary supplements they are taking or planning to take so their health care provider knows about other treatments that may affect bleeding risk (eg, aspirin, NSAIDs) or dabigatran exposure (eg, dronedarone, systemic ketoconazole).

Copyright © 2009 Wolters Kluwer Health.

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